Imidazole derivatives as MDR modulators

ABSTRACT

The present invention relates to polysubsituted imidazole having formula 1 ##STR1## These compounds are useful for restoring the sensitivity of multidrug resistant cells to cancer chemotherapeutic agents.

This is a continuation-in-part application of our co-pending applicationSer. No 08/890,911 filed on Jul. 09, 1997 now abandoned, the disclosureof which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides novel imidazole derivatives, novelpharmaceutical compositions containing same, methods of their use, andmethods of their manufacture. Such compounds are pharmacologicallyuseful for restoring the sensitivity of multidrug resistant cells tocancer chemotherapeutic agents.

BACKGROUND OF THE INVENTION

A major problem in the treatment of cancer is the emergence of tumorcell resistance to chemotherapeutic agents and the subsequent patientrelapse (Bradley et al.I, Cancer Res. 1989, 49, 2790-2796; Raderer andSscheitharer, Cancer 1993, 72, 3553-3563). These cancer victims may failto respond to any antitumor agent, since these tumor cells tend toexhibit clinical resistance to many drugs. This phenomenon is known asmulti-drug resistance (MDR). MDR is associated with certain alterationsin tumor cells resulting in reduced intracellular anticancer drugaccumulation, including reduced membrane permeability and increasedremoval of drug from the cell via an energy-dependent efflux mechanism.Studies of this mechanism have led to the characterization of genescapable of conferring resistance to chemotherapeutic agents. One ofthese genes, the P-glycoprotein or MDR1 gene, has been stronglyimplicated since overexpression of this gene can lead to resistance toanthracyclines, vinca alkaloids, and podophyllins, all importantchemotherapeutic agents. MDR1 encodes a 170 kDa membrane alycoporotein(gp-170 or Pgp) that acts as an ATP-dependent dfflux pump, transportinga number of unrelated organic compounds out of the cell (Juranka et al,FASEB J. 1989, 3, 2583-2592). The level of expression of gp-170 has beenshown to correlate with the degree of drug resistance (Raderer andSscheitharer, Cancer 1993, 72, 3553-3563). Gp-170 appears to act as apump that actively extrudes a wide variety of structurally unrelatedcompounds, including a full range of antineoplastic drugs. AnotherATP-dependent membrane efflux pump, the product of the MRP gene, hasalso been implicated in the MDR phenomenon (Krishnamachary and Center,Cancer Res. 1993, 53, 3658-3661), as have other ATP-dependent andenzymatic mechanisms.

Drugs of proven antitumor chemotherapeutic value to which MDR has beenobserved include vinblastine, vincristine, etoposide, teniposide,doxorubicin (adriamycin), daunorubicin, pliamycin (mithramycin), andactinomycin D (Jones et al, Cancer (Suppl)1993, 72, 3484-3488). Manytumors are intrinsically multidrug resistant (e.g., adenocarcinomas ofthe colon and kidney) while other tumors acquire MDR during the courseof therapy (e.g., neuroblastomas and childhood leukemias).

A variety of structurally diverse agents have been identified which canrestore partly or sometimes completely the normal drug sensitivity tosome MDR tumor cells. It is assumed that these chemosensitizers areeffective as a result of their ability to interfere with gp-170, causinga reversal in the increase in drug efflux. Among these agents arecalcium channel blockers (e.g., verapamil), calmodulin inhibitors (e.g.,trifluoperazine), antibiotica (e.g., erythromycin), cardiovascularagents(e.g., quinidine), noncytotoxic analogs of anthracyclines and vincaalkaloids, cyclosporin A and analogs thereof, FK-506 and analogsthereof, and derivatives of cyclopeptides (Lum et al, Cancer(Suppl)1993, 72, 3502-3514). However, at the present time, none of theseagents has provided a significant contribution to the chemotherapeuticindex for the treatment of cancer due to their significantpharmacologidal effects on other organ systems. An effective therapeuticagent for the reversal of MDR needs to have efficacy against themenbrane pump as well as lack of significant toxicity and othernonspecific pharmacological effects.

The present invention describes a family of novel substituted imidazolederivatives of Formula (1) that are effective in increasing thesensitivity of tumor cells resistant to anticancer chemotherapeuticagents, such as doxorubicin (DOX), taxol, vinblastine (VLB), andenhancing the sensitivity of multi-drug resistant cells. These compoundshave the effect of reducing the resistance of MDR tumor cells, andpotentiating the sensitivity of cells to antitumor drugs, such as DOX,taxol, VLB. These compounds are expected to have broad application inthe chemotherapy of cancer.

SUMMARY OF THE INVENTION

The novel compounds of this invention have the general structure (1)##STR2## and are capable of restoring sensitivity to multi-drugresistant tumor cells. It is an object of this invention to providecompounds that have sufficient activity to sensitize multi-drugresistant tumor cells to antineoplastic agents.

It is an additional object of this invention to provide a method ofsensitizing multi-drug resistant tumor cells using the novel compoundsof the present invention.

A further object is to provide a method of treatment of MDR ordrug-sensitive tumor cells by administering a sufficient amount of acompound of the present invention, prior to, together with, orsubsequent to the administration of an antitumor chemotherapeutic agent.A further object is to provide pharmaceutical compositions forincreasing the sensitivity of tumor cells to antitumor chemotherapeuticagents and thus for the treatment of tumors that are susceptible toanti-cancer chemotherapeutic agents but have become resistant to suchchemotherapy.

Definitions

As used herein, the term "attached" signifies a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art.

The terms "halogen" or "halo" include fluorine, chlorine, bromine, andiodine.

The term "alkyl" includes C₁ -C₁₁ straight chain saturated, C₁ -C₁₁,branched saturated, C₃ -C₈ cyclic saturated and C₁ -C₁₁ straight chainor branched saturated aliphatic hydrocarbon groups substituted with C₃-C₈ cyclic saturated aliphatic hydrocarbon groups having the specifiednumber of carbon atoms. For example, this definition shall include butis not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu),pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr),isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl,neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, methylcyclopropyl, and the like.

The term "alkenyl" includes C₂ -C₁₁ straight chain unsaturated, C₂ -C₁₁branched unsaturated, C₅ -C₈ unsaturated cyclic, and C₂ -C₁₁ straightchain or branched unsaturated aliphatic hydrocarbon groups substitutedwith C₃ -C8 cyclic saturated and unsaturated aliphatic hydrocarbongroups having the specified number of carbon atoms. Double bonds mayoccur in any stable point along the chain and the carbon-carbon doublebonds may have either the cis or trans configuration. For example, thisdefinition shall include but is not limited to ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl,butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like.

The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents an alkyl group as defined above having theindicated number of carbon atoms attached through an oxygen bridge.

The term "alkylthio" (e.g. methylthio, ethylthio, propylthio,cyclohexylthio and the like) represents an alkyl group as defined abovehaving the indicated number of carbon atoms attached through a sulfurbridge.

The term "alkylamino" (e.g. methylamino, diethylamino, butylamino,N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexylamino,pyrrolidinyl, piperidinyl and the like) represents one or two alkylgroups as defined above having the indicated number of carbon atomsattached through an amine bridge. The two alkyl groups maybe takentogether with the nitrogen to which they are attached forming a cyclicsystem containing 3 to 11 carbon atoms with at least one C₁ -C₁₁ alkyl,aryl C₀ -C₁₁ alkyl substituent.

The term "alkylaminoalkyl" represents an alkylamino group attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term "alkyloxy(alkyl)amino" (e.g. methoxy(methyl)amine,ethoxy(propyl)amine) represents an alkyloxy group as defined aboveattached through an amino group, the amino group itself having an alkylsubstituent.

The term "alkylcarbonyl" (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexylcarbonyl) represents an alkyl group as defined above having theindicated number of carbon atoms attached through a carbonyl group.

The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy) represents an alkylcarbonyl group as defined abovewherein the carbonyl is in turn attached through an oxygen. The term"alkylcarboxyalkyl" represents an alkylcarboxy group attached through analkyl group as defined above having the indicated number of carbonatoms.

The term "alkylcarbonylamino" (e.g. hexylcarbonylamino,cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl) representsan alkylcarbonyl group as defined above wherein the carbonyl is in turnattached through the nitrogen atom of an amino group. The nitrogen groupmay itself be substituted with an alkyl or aryl group.

The term "aryl" represents an unsubstituted, mono-, di- ortrisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromaticgroups covalently attached at any ring position capable of forming astable covalent bond, certain preferred points of attachment beingapparent to those skilled in the art (e.g., 3indolyl, 4-imidazolyl). Thearyl substituents are independently selected from the group consistingof halo, nitro, cyano, trihalomethyl, C₁₋₁₁ alkyl, aryl C₁₋₁₁ alkyl,C₀₋₁₁ alkyloxy C₀₋₁₁ alkyl, aryl C₀₋₁₁ alkyloxy C₀₋₁₁ alkyl, C₀₋₁₁alkylthio C₀₋₁₁ alkyl, aryl C₀₋₁₁ alkylthio C₀₋₁₁ alkyl, C₀₋₁₁alkylamino C₀₋₁₁ alkyl, aryl C₀₋₁₁ alkylamino C₀₋₁₁ alkyl, di(aryl C₁₋₁₁alkyl)amino C₀₋₁₁ alkyl, C₁₋₁₁ alkylcarbonyl C₀₋₁₁ alkyl, aryl C₁₋₁₁alkylcarbonyl C₀₋₁₁ alkyl, C₁₋₁₁ alkylcarboxy C₀₋₁₁ alkyl, aryl C₁₋₁₁alkylcarboxy C₀₋₁₁ alkyl, C₁₋₁₁ alkylcarbonylamino C₀₋₁₁ alkyl, arylC₁₋₁₁ alkylcarbonylamino C₀₋₁₁ alkyl, --C₀₋₁₁ alkylCOOR₁, --C₀₋₁₁alkylCONR₂ R₃ wherein R₁, R₂ and R₃ are independently selected fromhydrogen, C₁ -C₁₁ alkyl, aryl C₀ -C₁₁ alkyl, or R₂ and R₃ are takentogether with the nitrogen to which they are attached forming a cyclicsystem containing 3 to 8 carbon atoms with at least one C₁ -C₁₁ alkyl,aryl C₀ -C₁₁ alkyl substituent.

The definition of aryl includes but is not limited to phenyl, biphenyl,naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl,azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl,benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl,benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl,pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl,isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl,piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl,oxadiazolyl, thiadiazolyl.

The term "arylalkyl" (e.g. (4-hydroxyphenyl)ethyl,(2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group asdefined above attached through an alkyl group as defined above havingthe indicated number of carbon atoms.

The term "carbonyloxy" represents a carbonyl group attached through anoxygen bridge.

In the above definitions, the terms "alkyl" and "alkenyl" maybe usedinterchangeably in so far as a stable chemical entity is formed, asobvious to those skilled in the art.

The term "therapeutically effective amount" shall mean that amount ofdrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention have the general structure asdepicted in Formula (1) ##STR3## wherein the substituents R₁, R₂, R₃,and R₄ are defined as described in A and B below:

A. when R₁ is selected from the group consisting of:

(i) substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or

(ii) mono-, di-,and tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, thienyl wherein thesubstituents are selected from the group consisting of:

(a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or inwhich the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy,

(b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy, substituted C₂₋₆alkylthio, substituted C₂₋₆ alkoxycarbonyl, wherein the substituents areselected from the group consisting of C₁₋₆ alkoxy, C₁₋₆ alkylthio, or

(c) C₁₋₁₁ CO₂ R₅, C₁₋₁₁ CONHR₅, trans- CH═CHCO₂ R₅, or trans-CH═CHCONHR₅wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy;

then R₂ and R₃ are each independently selected from the group consistingof mono-, di, and tri-substituted phenyl wherein the substituents areindependently selected from:

(i) substituted C₁₋₆ alkyl,

(ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆alkenyloxy,

(iii) substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino,

(iv) C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino,

(v) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, N--C₁₋₆ alkylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,

wherein the substituents are selected from the group consisting of

(a) hydroxy, C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino,

(b) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or

(c) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, N--C₁₋₆ alkenylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,

or R₂ and R₃ taken together forming an aryl group such as phenyl,pyridyl, in which the aryl may be optionally substituted, wherein thesubstituents are defined as above in (i)-(v);

and R₄ is selected from the group consisting of:

(i) hydrogen;

(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; or

(iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl, thienyl in which the substituents areselected from A. (a-c); or

B. when R₁ is selected from the group consisting of:

Mono-,di-, and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selectedfrom the group consisting of phenyl, thienyl, and the substituents areselected from the group consisting of:

(a) trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkl and C₁₋₄ alkyloxy, C₁₋₄alkloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₀₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above,

(b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2alkenylsulfonyl ethenyl, trans-2- substituted alkylsulfonylethenyl, trans-2- substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above,

(c) C₁₋₆ CO₂ R₅, trans- CH═CHCO₂ R, C₁₋₆ CONHR₅, or trans-CH═CHCONHR₅,wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆ alkylaminoC₂₋₆ alkyl, di(C₀₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl,substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆ alkylamino C₂₋₆alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆alkylthio C₂₋₆ alkyl, in which the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,N--C₁₋₆ alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N--(C₁₋₆ alkoxyC₀₋₆ alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,

(d) C₁₋₆ CONR₆ R₇, or trans- CH═CHCONR₆ R₇, wherein R₆ and R₇ areindependently selected from the group consisting of C₁₋₆ alkyl, phenylC₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy C₂₋₆ alkyl, C₁₋₆alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl,di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substitutedC₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆ alkylamino C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthioC₂₋₆ alkyl, wherein the substituents are selected from the groupconsisting of pyrrolidino, piperidino, morpholino, piperazino, N--C₁₋₆alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,

(e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O) carbonyl C₂₋₆ alkenyl, in which R₇ isdefined as above 2(d)!,

(f) HO--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇ --_(O--C) ₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆ R₇ N--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH--C(O)--O--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₁₋₆ R₇ N--C(O)--O--C₁₋₆alkyl-C₂₋₆ alkenyl, R₇ O--C(O)--O--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇--C(O)--O--C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined asabove 2(d)!,

(g) R₇ --O--CO₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇ NH-- C₀₋₃ alkyl- C₃₋₆cycloalkan1-yl, R₆ R₇ N-- C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl, R₇NH--C(O)--O-- C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆ R₇ N--C(O)--O-- C₀₋₃ alky-C₃₋₆ cycloalkan-1-yl, R₇ O--C(O)--O--C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl,R₇ --C(O)--O-- C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl, R₇ O--C(O)--CO₀₋₃alkyl- C₃₋₆ cycloalkan-1-yl, wherein R₇ and is defined as above 2(d)!;

then R₂ and R₃ are each independently selected from the group consistingof

(1) hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₁₋₆ alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino,

(2) mono-, di-, and tri-substituted phenyl wherein the substituents areindependently selected from:

(i) halo, trifluoromethyl, substituted C₁₋₆ alkyl,

(ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,substituted C₃₋₆ alkenyloxy,

(iii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino,di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substitutedC₃₋₆ alkenyl)amino,or

(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, N--C₁₋₆ alkenylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,

wherein the substituents are selected from the group consisting of

(a) hydrogen, hydroxy, halo, trifluoromethyl,

(b) C₁₋₆ alkylalkoxy, C₀₋₆ alkylamino, C₁₋₆ alkylthio,

(c) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, C₃₋₆ alkenylthio, or

(d) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, N--C₁₋₆ alkenylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;

with the proviso that at least one of R₂ and R₃ group be selected from B(2)! and the phenyl and the substituents be selected from (ii)-(v)above; or R₂ and R₃ taken together forming an aryl group such as phenyl,pyridyl, in which the aryl may be optionally substituted, wherein thesubstituents are defined as above in (i)-(iv);

and R₄ is selected from the group consisting of:

(a) hydrogen;

(b) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of hydrogen,hydroxy, C₁₋₆ allyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl and the substituents are selected from(ii)-(iv); or

(c) aryl C₀₋₁₁ alkyl wherein the aryl group is selected from phenyl,imidazolyl, furyl, thienyl.

Novel compounds of the present invention include but are not limited tothe following compounds:

2- trans-2-(2-benzoxazolyl)ethenylphenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4N-methylaminophenyl)imidazole,

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-diethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole,

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N-disopropylaminophenyl)-5-(4-N-methylaminophenyl)imidazole,

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N-methylaminophenyl)-5-(4pyrrolidinophenyl)imidazole,

2- trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-4(2-methoxyethylamino)phenyl!imidazole,

2- trans-2-(2-benzthiazolyl)ethenylphenyl!-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole,

2-trans-2-(2-benzthiazolyl)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4N-methylaminophenyl)imidazole,

2- trans-2-(2-cyano)ethenylphenyl!-4, 5-(4-N,N-dimethylaminophenyl)imidazole,

2- trans-2-(2-cyano)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-4-N-(2methoxyethyl)amino)phenyl! imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N,N-diallylaminophenyl)-5-(4fluoro-phenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-methylaminophenyl)-5-(4-pyrrolidinophenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-methylaminophenyl)-5-(4-piperidinophenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-4-N,N-di(2-methoxyethyl)aminophenyl!-5-(4-N-methylaminophenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-4-(1-imidazolyl)phenyl!-5-(4-N-methylaminophenyl) imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4,5-bis (4-N-morpholinophenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N,N-dimethylaminophenyl)-5-(4N-morpholinophenyl)imidazole,

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-methylaminophenyl)-5-(4-N-morpholinophenyl)imidazole:

2- 4-(3-methoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N-dimethylaminophenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole,

2- 4-(3-benzyloxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-phenoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4-N-methylaminopheny) imidazole,

2-{4- 3-(3,4-dimethoxy-phenoxy)-trans-1-propen-1-yl!phenyl}-4-(4-N-dimethylaminophenyl)-5-(4-N-methylaminopheny)imidazole,

2- 4-(3-N,N-diethylamino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-N-morpholino-trans-1-propen-1-yl)phenyl!-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-N-piperidino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-N,N-dimethylamino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2-{4- 3-(2-methoxy-ethoxy)-trans-1-propen-1-yl!phenyl}-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-butoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-diethylaminophenyl) imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-diethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole,

2- 4-(3-methoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-pyrrolidinophenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-pyrrolidinophenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4-pyrrolidinophenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5-(4-pyrrolidinophenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N-morpholinophenyl) imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4-N-morpholinophenyl)imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5-(4-N-morpholinophenyl)imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5-(4-N-isopropylaminophenyl)imidazole,

2- 4-trans-(2-methanesulfonyl-ethenyl)-phenyl!-4,5-bis (4-N,N-dimethylaminophenyl) imidazole,

2-(4-N-morpholinophenyl)-4,5-bis (4-N,N-dimethylaminophenyl) imidazole,

2- 4-(5-ethylcarboxyisoxazol-3-yl)-phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2-4-trans-(2-methoxycarbonyl-ethenyl)phenyl!-4-(p-tolyl)-5-(4-N,N-diethylaminomethylphenyl)imidazole,

2- 4-trans-(2-methoxycarbonyl-ethenyl)phenyl!-4,5-bis(4-N,N-diethylaminomethylphenyl) imidazole,

2- 4-trans-(2-methoxycarbonyl)cyclopropan-1-yl!-4,5-bis(4-N,N-diethylaminomethylphenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-dimethoxyphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-diethoxyphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-diisopropyloxyphenyl) imidazole,

1-(3-imidazole-1-yl-propyl)-2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4dimethoxyphenyl)imidazole,

1 -(3-imidazole-1-yl-propyl)-2- 4-(3-ethoxy-trans-1-propen- 1-yl)phenyl!-4,5-bis (4-diethoxyphenyl) imidazole,

1-(3-imidazole-1-yl-propyl)-2- 4-(3-ethoxy-trans- 1 -propen-1-yl)phenyl!-4,5-bis (4-diisopropyloxyphenyl) imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N, N-diethylphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-methoxyphenyl)imidazole,

2- 4-trans-(2-N,N-dimethylcarbonyl)-ethenyl!phenyl}-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-hydroxy-trans-1-propen-1-yl)phenyl!-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole,

1 -methyl-2- 4-(3-hydroxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-pivalate-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-methylcarbonyl-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole,

2- 4-(3-methylcarbonyl-trans-1-propen-1-yl)phenyl!-5-methoxybenzimidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis-(4-N-isopropylaminophenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-ethylaminophenyl)-5-(4-N-isopropylaminophenyl) imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-fluorophenyl)-5-(4-N-isopropylaminophenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dipropylphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-isopropylphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-isobutylphenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-morpholinophenyl)imidazole,

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4- 4-N-(N'-ethyl)-piperizanophenyl) imidazole,

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-morpholinophenyl)-5-methyl-imidazole.

Preferred compositions of the invention include compositions comprisingcompounds as defined above in structural formula (1) (orpharmaceutically acceptable salts, prodrugs, esters, or solvates ofthese compounds) in admixture with a pharmaceutically acceptablediluent, adjuvent, or carrier.

Provided according to the invention, therefore, are novel compoundswhich modulate multi-drug resistance (MDR) in vitro in CEM/VLB1000 humancells.

Provided according to the invention, therefore, are novel compoundswhich modulate multi-drug resistance (MDR) in murine models withP388-ADR human cells.

Provided according to the invention, therefore, are novel compoundswhich modulate multi-drug resistance (MDR) in murine models withP388-ADR ascites human tumors.

Another aspect of the present invention provides compositions comprisingMDR modulating compounds of the invention suitable for administration toa mammalian host.

As a preferred embodiment, the compounds of the invention may be used astherapeutics to modulate MDR in cancer patients who show resistance toanticancer chemotherapeutic agents such as DOX, taxol and VLB.

Preferred embodiments of the invention further include use of compoundsof the invention in pharmaceutical preparations to increase thesensitization of MDR cancer cells in patients who show resistance toanticancer chemotherapeutic agents such as DOX, taxol and VLB.

Compounds of the invention may additionally be used for treatment ormodulation of MDR in animals, including commercially important animals.

Provided according to this invention are methods of sensitizingmultidrug resistant tumor cells using the novel compounds of the presentinvention.

Provided according to this invention are methods of treatment of MDR ordrug-sensitive tumor cells by administering a sufficient amount of acompound of the present invention, prior to, together with, orsubsequent to the administration of an antitumor chemotherapeutic agent.

Provided according to this invention are pharmaceutical compositions forincreasing the sensitivity of tumor cells to antitumor chemotherapeuticagents and thus for the treatment of tumors that are susceptible toanti-cancer chemotherapeutic agents but have become resistant to suchchemotherapy.

The invention further provides methods for making compounds of Formula(1) of the present invention having MDR modulating activity. Thecompounds of Formula (1) maybe prepared by procedures known to thoseskilled in the art from known compounds or readily preparableintermediates.

The following Examples are intended to illustrate the preparation ofcompounds of Formula 1, and as such are not intended to limit theinvention as set forth in the claims appended thereto. Furthermore, thecompounds described in the following examples are not to be construed asforming the only genus that is considered as the invention, and anycombination of the compounds or their moieties may itself form a genus.The structure and purity of all final products were assured ny at leastone of the following methods: thin -layer chromatography (TLC), massspectroscopy, nuclear magnetic resonance (NMR) spectroscopy. NMR data isin the form of delta (d) values for major diagnostic protons, given inparts per million (ppm) relative to tetramethylsilane (TMS) as internalstandard, determined at 400 MHz in deuterated sovents such asdeuteriochloroform (CDCl₃), and deuteriomethanol (CD₃ OD); conventionalabbreviations used for signal shape are: s, singlet; d, doublet; t,triplet; dd, double of doublet; dt, double of triplet; m, multiplet;br., broad; etc. The following abbreviations have also been used: mL(milliliter), g (gram), mg (milligram), mol (moles), mmol (millimoles),equiv (equivalent).

The procedures employed to synthesize compounds depicted in Formula 1are as follows:

Method A. General Procedure for the Preparation of Diones:

There are three methods by which these diones were synthesized, namely:

Method 1

4,4'-difluorodione 4 was reacted with a series of amines (R₁ R₂ NH)using an appropriate base such as K₂ CO₃, Na₂ CO₃, Et₃ N,diisopropylethylamine (DIEA), etc., at elevated temperature (60°-150°C.) in an appropriate solvent such as alcohol, acetonitrile,N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) to provide themono-amino-diones 2 (procedure Bader et al J. Org. Chem. 1966, 31,2319). The mono-amino-diones 2 were further reacted with another amine(R₃ R₄ NH) under the same conditions to afford the desired diones 3 asshown in Scheme 1. This procedure allows for the synthesis ofunsymmetrical diones 6 (wherein R₁ R₂ NH is different from R₃ R₄ NH).This chemistry was carried out using 1-1.5 equivalent of R₁ R₂ NH andupon the completion of the reaction another equivalent of differentamine (R₃ R₄ NH) was added to the reaction mixture to provide thedesired unsymmetrical diones (Scheme 1). ##STR4##

Unsymmetrcal diones were prepared according to the following procedure:To a solution of 4,4'-difluorobenzil in DMSO (0.5M) was added 1.2 equivof amine R₁ R₂ NH and 2 equiv of potassium carbonate. The resultingmixture was stirred in a 90° C. oil bath for 6-15 hours (TLCmonitoring). After completion, the mixture was diluted with ether andextracted with 3M hydrochloric acid (×5) to remove the small amount ofproduct resulted from the di-displacement. The organic layer was thenwashed with 6M hydrochloric acid until no more desired product in theether layer (5 times). The aqueous layer was neutralized to pH 8 with 6Maqueous sodium hydroxide and it was extracted with dichloromethane. Theorganic layers were dried (Na₂ SO₄), evaporated to give4-amino,4'-fluorobenzil. This procedure was repeated with the secondamine R₃ R₄ NH (normally 2-3 equiv) and a simple workup by diluting thereaction mixture into ether and washed with water to remove DMSO. 4,4'-diaminobenzil was thus obtained (50-90% overall depending aminesused) in high purity.

For symmetrical diones (wherein R₁ R₂ NH is equal to R₂ R₃ NH) thefollowing procedure was followed:

To a solution of 4,4'-difluorobenzil in DMSO (0.5M) was added 2-3 equivof amine R₁ R₂ NH and 2-3 equiv of potassium carbonate. The resultingmixture was stirred in an 90° C. oil bath for 6-15 hours (TLCmonitoring). After completion, the mixture was diluted into ether andwashed with water to remove DMSO. The desired diones 6 were obtained(50-90% overall depending amines used) in high purity. The followingexamples have been synthesized according to method 1:

EXAMPLES

4) 4-N,N-dimethylamino-4'-methylaminobenzil ##STR5##

¹ H NMR (400 MHz, CDCl₃) 67 2.80 (s, 3 H), 3.03 (s, 6 H), 4.48 (br s, 1H),

6.48 (d, 2 H), 6.59 (d, 2 H), 7.75 (d, 2 H), 7.79 (d, 2 H).

5) 4-N,N-diethylamino-4'-methylaminobenzil ##STR6##

¹ H NMR (400 MHz, CDCl₃) δ1.15 (t, 6 H), 2.85 (s, 3 H), 3.37 (q, 4 H),4.40 (s, 1 H), 6.50 (d, 2 H), 6.57 (d, 2 H), 7.78 (d, 4 H).

6) 4-N-isopropylamino-4'-methylaminobenzil ##STR7##

¹ H NMR (400 MHz, CDCl₃) 67 1.18 (d, 6 H), 2.83 (d, 3 H), 3.65 (m, 1 H),4.28 (br d, 1 H), 4.54 (br s, 1 H), 6.47 (d, 2 H), 6.49 (d, 2 H), 7.74(d, 2 H), 7.76 (d, 2 H).

7) 4-pyrrolidino-4'-methylaminobenzil ##STR8##

¹ H NMR (400 MHz, CDCl₃) 67 1.98 (m, 4 H), 2.83 (s, 3 H), 3.32 (m, 4 H),4.48 (s, 1 H), 6.46 (d, 2 H), 6.48 (d, 2 H), 7.76 (d, 2 H), 7.78 (d, 2H).

8) 4-piperidino-4'-methylaminobenzil ##STR9##

¹ H NMR (400 MHz, CDCl₃) δ1.61 (br s, 6 H), 2.83 (d, 3 H), 3.35 (br s, 4H), 4.48 (s, 1 H), 6.49 (d, 2 H), 6.77 (d, 2 H), 7.76 (d, 2 H), 7.78 (d,2 H).

9) 4-N,N-dimnethylamino-4'-N-(2-methoxyethyl)aminobenzil ##STR10##

¹ H NMR (400 MHz, CDCl₃) δ3.03 (s, 6 H), 3.32 (m, 5 H), 3.56 (t, 2 H),4.66 (s, 1 H), 6.53 (d, 2 H), 6.60 (d, 2 H), 7.77 (d, 2 H), 7.80 (d, 2H).

10) 4-N,N-di-(2-methoxyethyl)amino-4'-methylaminobenzil ##STR11##

¹ H NMR (400 MHz, CDCl₃) δ2.82 (d, 3 H), 3.29 (s, 6 H), 3.50 (t, 4 H),3.60 (t, 4 H), 4.48 (br s, 1 H), 6.49 (d, 2 H), 6.64 (d, 2 H), 7.76 (d,4 H).

11) 4-(imidazole-1-yl)-4'-N-(2-methoxyethyl)aminobenzil ##STR12##

¹ H NMR (400 MHz, CD₃ OD) δ2.82 (s, 3 H), 6.59 (d, 2 H), 7.15 (s, 1 H),7.69 (m, 3 H), 7.76 (d, 2 H), 8.05 (d, 2 H), 8.29 (s, 1 H).

12) 4,4'-bis(4-morpholino)benzi ##STR13##

¹ H NMR (400 MHz, CDCl₃) δ3.30 (m, 8 H), 3.80 (m, 8 H), 6.80 (d, 4 H),7.82 (d, 4 H).

13) 4-N,N-dimethylamino-4'-(4-morpholino)benzil ##STR14##

¹ H NMR (400 MHz, CDCl₃) δ3.04 (s, 6 H), 3.30 (m, 4 H), 3.81 (m, 4 H),6.61 (d, 2 H), 6.82 (d, 2 H), 7.81 (d, 2 H), 7.85 (d, 2 H).

14) 4-N-methylamino-4'-(4-morpholino)benzil ##STR15##

¹ H NMR (400 MHz, CDCl₃) 67 2.90 (d, 3 H), 3.30 (m, 4 H), 3.80 (m, 4 H),4.42 (m, 1 H), 6.52 (d, 2 H), 6.82 (d, 2 H), 7.78 (d, 2 H), 7.84 (d, 2H).

15) 4-N,N-diallylamino-4'-fluorobenzil ##STR16##

¹ H NMR (400 MHz, CDCl₃) 67 3.95 (d, 4 H), 5.12 (m, 4 H), 5.78 (m, 2 H),6.63 (d, 2 H), 7.09 (d, 1 H), 7.10 (d, 1 H), 7.75 (d, 2 H), 7.96 (m, 2H). ##STR17##

Compound 19 and 20 were prepared according to Venugopalan et al (IndianJ. Chem. 1991, 30B, 777-783).

Compound 19 has: ¹ H NMR (400 MHz, CDCl₃) δ1.00 (t, 6 H), 2.39 (s, 3 H),2.50 (q, 4 H), 3.60 (s, 3 H), 3.61 (s, 2 H), 7.26 (d, 2 H), 7.45 (d, 2H), 7.83 (d, 2 H), 7.86 (d, 2 H).

Compound 20 has: ¹ H NMR (400 MHz, CDCl₃) δ1.00 (t, 12 H), 2.50 (q, 8H), 3.60 (s, 4 H), 7.46 (d, 4 H), 7.87 (d, 4 H).

Method B. General method for the synthesis of aldehydes ##STR18##

Aldehydes 23 were prepared according to Houpis et al (J Org. Chem. 1993,58, 3176-3178).

EXAMPLES

25) p- trans-2-(benzoxazol-2-yl)ethenyl!benzaldehyde ##STR19##

To a solution of terephthaldehyde momo (diethyl acetal) 21 (5.000 g, 24mmol.), 2-methylbenzoxazole in 5:1 THF-t-BuOH (77.4 mL) cooled at -5°C., was added t-BuOK in THF (1.0M, 36.0 mL, 36.0 mmol.) in such a rateto keep the internal temperature of the reaction below 0° C. (ca. 10min). The resulting mixture was stirred under nitrogen overnight duringwhich time the temperature rised up to room tempt. It was then dilutedwith ethyl acetate and washed with sat. sodium bicarbonate. The organiclayer was dried (Na₂ SO₄) and evaporated to give a brown oily solid. Itwas then dissolved in boiling methanol (50 mL) and cooled to room tempt.The white solid was precipitated out after the addition of water (25 mL)and the solid was collectted. The acetal thus obtained was hydrolysed bystirring the product in 3:1 THF-1N HCl solution for 10 min. The mixturewas extracted with ethyl acetate, the organic layers were washed withsat. sodium bicarbonate, brine and dried (Na₂ SO₄). Evaporation gave aslightly yellow solid 25, 4.43 g (74% overall yield). Compound 25 has: ¹H NMR (400 MHz, CDCl₃) δ7.14 (d, 1 H), 7.31 (m, 2 H), 7.49 (m, 1 H),7.68 (m, 3 H), 7.75 (d, 1 H), 7.86 (d, 2 H), 10.00 (s, 1 H).

26) p- trans-2-(benzthiazol-2-yl)ethenyl!benzaldehyde ##STR20##

Compound 26 has: ¹ H NMR (400 MHz, CDCl₃) δ7.36 (dd, 1 H), 7.44 (dd, 1H), 7.50 (d, 2 H), 7.68 (d,, 2 H), 7.84 (d, 1 H), 7.88 (d, 2 H), 7.98(d, 1 H), 9.98 (s, 1 H). ##STR21##

By allowing a compound (27) wherein Ar is defined as above to react withcompound (28) wherein EWG is esters and other electron withdrawinggroups, under the following condintions, the desired compounds (29) canbe obtained.

These reactions may be carried out neat or in a solvent such asdimethylformamide (DMF), tetrahydrofuran (THF), and toluene in thepresence of a catalyst (e.g. Pd(OAc)₂, Pd(PPh₃)₄, Pd₂ dba₃), a ligand(e.g. Ph₃ P, Ph₃ As, (o-tolyl)₃ P) and a base (e.g. K₂ CO₃, CsCO₃, Et₃N) at temperatures ranging from 23° C. to 130° C., for 1 to 60 hours.

EXAMPLES

32) Methyl 4-formyl trans-cinnamate ##STR22##

Prepared according to Patel et al (J. Org. Chem., 1977, 42, 3903).

Compound 32 has: ¹ H NMR (400 MHz, CDCl₃) δ3.78 (s, 3 H), 6.50 (d, 1 H),7.63 (m, 3 H), 7.85 (d, 2 H), 9.98 (s, 1 H)..

33) p- trans-2- (methylsulfonyl)ethenyl!benzaldehyde ##STR23##

Compound 33 has: ¹ H NMR (400 MHz, CDCl₃) δ3.00 (s, 3 H), 7.01 (d, 1 H),7.63 (d, 1 H), 7.64 (d, 2 H), 7.90 (d, 2 H).

Method B-3

36) p- trans-2-(cyano)ethenyl!benzaldehyde ##STR24##

Amonia (0.5M in dioxane, 45 mL, 22.5 mmol.) was added to a suspension of34 2.10 g, 12 mmol.), EDCI (2.37 g, 14.4 mmol.) and DMAP (0.293 g, 2.4mmol.) in dichloromethane (50 mL). The resulting mixture was stirred atroom tempt overnight. It was then diluted with dichloromethane andwashed with 1.0 M hydrochloric acid, followed by sat. sodiumbicarbonate. The organic layer was dried (Na₂ SO₄) and evaporated togive 1.244 g of compound 35 as a sightly yellow solid.

To a solution of Compound 35 (340 mg, 1.94 mmol.) in dichloromethane(20.0 mL) was added triethylamine (1.62 mL, 11.64 mmol.),thriphenylphosphine (1.5 g, 5.8 mmol.) and hexachloroethane (1.37 g, 5.8mmol.). The resulting mixture was stirred at room temperature for 10 minand evaporated. Flash chromatography of the residue (silica, 2.0×10 cm)by using 20 and 30% ethyl acetate--hexanes gave compound 36, 118 mg.Compound 36 has: 1 H NMR (400 MHz, CDCl₃) δ5.98 (d, 1 H), 7.57 (d, 2 H),7.61 (d, 1 H), 7.87 (d, 2 H), 1.00 (s, 1 H). ##STR25##

A solution of aldehyde 37 (2.3 g, 12.1 mmol), ethylene glycol (1.35 mL,24.2 mmol) , and p-toluenesulfonic acid (10 mg, catalytic amount) inbenzene (30.0 mL) was refluxed for 2 h. Then it was diluted with ethylacetate and washed with sat. aqueous sodium bicarbonate and brine, dried(Na₂ SO₄), evaporated. The crude material thus obtained was dissolved indichloromethane (DCM, 100.0 mL) and cooled to -78° C. DIBAL-H (1.0M inDCM, 45 mL, 45.0 mmol) was added over 20 min. Aqueous NaOH (1.0M, 100mL) was added and the mixture was warmed to room temperature (23° C.)and the layers were separated. The aqueous layer was extracted with DCM(×3), and the combined organic layers were dried (Na₂ SO₄) andevaporated. Flash chromatography of the residue over silica gel gave thedesired allylic alcohol 37. Compound 37 has: ¹ H NMR (400 MHz, CDCl₃)δ4.00 (d, 2 H), 4.10 (m, 2 H), 4.30 (d, 2 H), 6.35 (dt, 1 H), 6.60 (d, 1H), 7.48 (m, 4 H).

Alkylation of allylic alcohol 38 with alkyl iodide and sodium hydride inTHF following the standard procedure (Jung, M. E. et aL, TetrahedronLett., 1989, 30, 641) and hydrolysis of the resulting acetal with 1Naqueous HCl gave the corresponding allylic ether 39.

EXAMPLES

40) p- (3-methoxy-trans-1-propen-1-yl) benzaldehyde ##STR26##

Compound 40 has: ¹ H NMR (400 MHz, CDCl₃) δ3.20 (s, 3 H), 4.10 (d, 2 H),6.40 (dt, 1 H), 6.64 (d, 1 H), 7.49 (d, 2 H), 7.80 (d, 2 H).

41) p-(3-ethoxy-trans-1-propen-1-yl) benzaldehyde ##STR27##

Compound 41 has: ¹ H NMR (400 MHz, CDCl₃) δ1.23 (t, 3 H), 3.54 (q, 2 H),4.14 (d, 2 H), 6.42 (dt, 1 H), 6.64 (d, 1 H), 7.49 (d, 2 H), 7.79 (d, 2H).

42) p-(3-benzyloxy-trans-1-propen-1-yl) benzaldehyde ##STR28##

Compound 42 has: ¹ H NMR (400 MHz, CDCl₃) δ4.20 (d, 2 H), 4.56 (s, 2 H),6.46 (dt, 1 H), 6.67 (d, 1 H), 7.34 (m, 5 H), 7.49 (d, 2 H), 7.79 (d, 2H).

43) p-(3-butyloxy-trans-1-propen-1-yl) benzaldehyde ##STR29##

Compound 43 has: ¹ H NMR (400 MHz, CDCl₃) δ0.90 (t, 3 H), 1.39 (m, 2 H),1.57 (m, 2 H), 3.47 (t, 2 H), 4.13 (d, 2 H), 6.43 (m, 1 H), 6.64 (d, 1H), 7.49 (d, 2 H), 7.79 (d, 2 H), 9.94 (s, 1 H).

44) p- 3-(2-methoxyethyl)-trans-1-propen-1-yl) !benzaldehyde ##STR30##

Compound 44 has: ¹ H NMR (400 MHz, CDCl₃) δ3.38 (s, 3 H), 3.55 (m, 2 H),3.64 (m, 2 H), 4.20 (d, 2 H), 6.43 (m, 1 H), 6.64 (d, 1 H), 7.48 (d, 2H), 7.79 (d, 2 H), 9.94 (s, 1 H).

Method B-5

46) p-(3-phenoxy-trans-1-propen-1-yl) benzaldehyde ##STR31##

Carbon tetrabromide (723 mg, 2.18 mmol) was added, in one prtion, to asolution of allylic alcohol 38 (300 mg, 1.45 mmol), andtriphenylphosphine (456 mg, 1.75 mmol) in DCM at room temperature (23°C.). After 2 min, sat aqueous sodium bicarbonate was added and thelayers were separated. The aqueous layer was extracted with DCM once andthe combined organic layers were dried (Na₂ SO₄), and evaporated. Flashchromatography of the residue over silica gel gave a white solid 344 mg(88%). Allylic bromide 45 has: ¹ H NMR (400 MHz, CDCl₃) δ4.20 (d, 2 H),4.56 (s, 2 H), 6.46 (dt, 1 H), 6.67 (d, 1 H), 7.34 (m, 5 H), 7.49 (d, 2H), 7.79 (d, 2 H).

The mixture of allylic bromide 45 (50 mg, 0.185 mmol), phenol (35 mg,0.37 mmol), and sodium hydride (excess) in THF (2.0 mL) was heated at 50° C. for 5 h. 1N aqueous HCl was added after cooling down to 23° C., 20min later, the mixture ws diluted with ethyl acetate and washed with 1NNaOH. The organic layer was dried (Na₂ SO₄), and evaporated.Purification of the residue on preparative TLC gave the desired aldehyde46, 24 mg, as a white solid. Compound 46 has: ¹ H NMR (400 MHz, CDCl₃)δ4.70 (d, 2 H), 6.55 (dt, 1 H), 6.77 (d, 1 H), 6.94 (m, 3 H), 7.28 (m, 2H), 7.51 (d, 2 H), 7.81 (d, 2 H), 9.98 (s, 1 H).

47) p- 3-(3,4-dimethoxyphenoxy)-trans-1-propen-1-yl) benzaldehyde##STR32##

Compound 47 has: ¹ H NMR (400 MHz, CDCl₃) δ3.80 (s, 3 H), 3.82 (s, 3 H),4.63 (d, 2 H), 6.44 (m, 1 H), 6.54 (m, 2 H), 6.75 (m, 2 H), 7.50 (d, 2H), 7.79 (d, 2 H), 9.96 (s, 1 H).

Method B-6

48) p- 3-(1-morpholino)-trans-1-propen-1-yl! benzaldehyde ##STR33##

Morpholine (82 mL, 0.945 mmol) was added to a solution of allylicbromide 45 in acetonitrile (3.0 mL). 30 min later, 1N aqueous HCl wasadded and the resulting mixture was stirred for 20 min. It was thendiluted with ethyl acetate and washed with sat. aqueous Na₂ CO₃, dried(Na₂ SO₄). Evaporation off the solvents gave the desired product 48, 55mg. Compound 48 has: ¹ H NMR (400 MHz, CDCl₃) δ2.50 (m, 4 H), 3.20 (d, 2H), 3.64 (m, 4 H), 6.46 (m, 1 H), 6.65 (d, 1 H), 7.58 (d, 2 H), 7.82(d,2 H), 9.92 (s, 1 H).

49) p- 3-(1-piperidino) -trans-1-propen-1-yl! benzaldehyde ##STR34##

Compound 49 has: ¹ H NMR (400 MHz, CDCl₃) δ1.24 (m, 2 H), 1.60 (m, 4 H),2.50 (m, 4 H), 3.18 (d, 2 H), 6.46 (m, 1 H), 6.64 (d, 1 H), 7.58 (d, 2H), 7.82(d, 2 H), 9.92 (s, 1 H).

50) p-(3-N,N-dimethylamino-trans-1-propen-1-yl) benzaldehyde ##STR35##

Compound 50 has: ¹ H NMR (400 MHz, CDCl₃) δ2.30 (s, 6 H), 3.18 (d, 2 H),6.46 (m, 1 H), 6.64 (d, 1 H), 7.58 (d, 2 H), 7.82(d, 2 H), 9.92 (s, 1H).

Method B-7

51) p-(3-N,N-diethylcarbamate-trans-1-propen-1-yl) benzaldehyde##STR36##

Carbonyl diimidazole (66 mg, 0.407 mmol) was added to a solution ofallylic alcohol 38 (42 mg, 0.204 mmol) in THF. The resulting mixture wasstirred for 1 h at 23° C. and diethylamine (63 mL, 0.612 mmol). It wasthen heated up to 60 ° C. for overnight. 1N HCl was then added and theresulting mixture was stirred for 20 min. It was then diluted with ethylacetate and washed with water. The organic layer was dried andevaporated. The crude material (30 mg) was chromatographically pure.Compound 51 has: ¹ H NMR (400 MHz, CDCl₃) δ1.10 (t, 6 H), 3.28 (m, 4 H),4.75 (d, 2 H), 6.44 (m, 1 H), 6.62 (d, 1 H), 7.50 (d, 2 H), 7.80 (d, 2H), 9.95 (s, 1 H).

Method B-8

52) p- trans-(2-methoxycarbonylcyclopropan-1-yl!benzaldehyde ##STR37##

Diazomethane (0.3 M in Et₂ O, 8.6 mL, 2.6 mmol) was added to asuspension of compound 37 (123 mg, 0.64 mmol), palladium acetate(catalytic amount) in ether (1.0 mL). After stirring at 23° C.overnight, it was quenched with acetic acid. The mixture was dilutedwith DCM, washed with sat. aqueous sodium carbonate, and dried (Na₂SO₄). Evaporation off the solvents gave the desired compound as an oil(99 mg). Compound 52 has: ¹ H NMR (400 MHz, CDCl₃) δ1.35 (m, 1 H), 1.60(m, 1 H), 1.92 (m, 1 H), 2.50 (m, 1 H), 3.64 (s, 3 H), 7.18 (d, 2 H),7.78 (d, 2 H), 9.90 (s, 1 H).

Method C. General Procedure for the Preparation of Imidazoles:

Method 1 ##STR38##

Imidazoles 55 were synthesed according to modified literature procedure(Krieg et al Z Naturforsch teil 1967, 22b, 132).

The proper dione (3.04 mmol.) and aldehyde (4.56 mmol.) were placed inacetic acid (5.85 mL) and ammonium acetate (30.4 mmol.) was placed inacetic acid (1.75 mL) in a separated reaction flask. Both of the flaskswere heated in an preheated oil bath (140° C.). As soon as the solids inthe two flasks were dissolved, poured the hot solution of ammoniumacetate in acetic acid into the other flask which contains the aldehydeand dione. The resulting mixture was heated at 140° C. for 40 min. Itwas then cooled to room temperature. The pH of solution was adjusted to0.8 using 3.0M hydrochloric acid. It was then extracted with ether (5times) to remove the unreacted aldehyde and dione). The aqueous layerwas neutralized to pH 8 with 3M sodium hydroxide and extracted withmethylenechloride (3 times). The organic layers were dried (N₂ SO₄) andevaporated to give the corresponding imidazole compound.

EXAMPLE 56

2- trans-2-(2-benzoxazolyl)ethenylphenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR39##

¹ H NMR (400 MHz, CDCl₃) δ2.95 (s, 12 H), 6.55 (d, 4 H), 6.90 (d, 1 H),7.21 (m, 6 H), 7.39 (m, 1 H), 7.50 (m, 3 H), 7.63 (d, 1 H), 7.83 (d, 2H); ESIMS, m/z for C₃₄ H₃₁ ON₅ M+H!⁺ : 526.

EXAMPLE 57

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole: ##STR40##

¹ H NMR (400 MHz, CD₃ OD) δ2.78 (s, 3 H), 2.95 (s, 6 H), 6.51 (d, 2 H),6.63 (d, 2 H), 6.98 (d, 2 H), 7.36 (in, 8 H), 7.64 (m, 1 H), 7.70 (d, 1H), 7.85 (d, 2 H); ESIMS, m/z for C₃₃ H₂₉ ON₅ M+H!⁺ : 512.

EXAMPLE 58

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-diethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole: ##STR41##

¹ H NMR (400 MHz, CDCl₃) δ1.12 (t, 6 H), 2.80 (s, 3 H), 3.31 (q, 4 H),6.53 (d, 2 H), 6.59 (d, 2 H), 6.98 (d, 1 H), 7.29 (m, 2 H), 7.39 (m, 4H), 7.49 (m, 1 H), 7.52 (d, 2 H), 7.65 (m, 1 H), 7.70 (d, 1 H), 7.86 (d,2 H); ESIMS, m/z for C₃₅ H₃₃ ON₅ M+H!⁺ : 540.

EXAMPLE 59

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N-disopropylaminophenyl)-5-(4-N-methylaminophenyl)imidazole: ##STR42##

¹ H NMR (400 MHz, CDCl₃) δ1.14 (s, 3 H), 1.16 (s, 3 H), 2.76 (s, 3 H),3.56 (m, 1 H), 6.48 (m, 4 H), 6.92 (d, 1 H), 7.31 (m, 6 H), 7.46 (m, 3H), 7.62 (m, 1 H), 7.66 (d, 1 H), 7.83 (d, 2 H); ESIMS, m/z for C₃₄ H₃ ₁ON₅ M+H!⁺ : 526.

EXAMPLE 60

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N-methylaminophenyl)-5-(4-pyrrolidinophenyl)imidazole: ##STR43##

¹ H NMR (400 MHz, CDCl₃) δ1.95 (br s, 4 H), 2.80 (br s, 3 H), 3.30 (brs, 4 H), 6.50 (m, 4 H), 7.00 (br d, 1 H), 7.22-7.90 (m, 13 H); ESIMS,m/z for C₃₅ H₃₁ ON₅ M+H!⁺ : 538.

EXAMPLE 61

2-trans-2-(2-benzoxazolyl)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-4-(2-methoxyethylamino)phenyl!imidazole: ##STR44##

¹ H NMR (400 MHz, CDCl₃) δ2.90 (s, 6 H), 3.24 (br s, 2 H), 3.35 (s, 3H), 3.56 (t, 2 H), 6.54 (d, 2 H), 6.63 (d, 2 H), 6.97 (d, 1 H),7.24-7.44 (m, 6 H), 7.49 (m, 3 H), 7.64 (m, 1 H), 7.69 (s, 1 H), 7.85(d, 2 H); ESIMS, m/z for C₃₅ H₃₃ O₂ N₅ M+H!⁺ : 556.

EXAMPLE 62

2- trans-2-(2-benzthiazolyl)ethenylphenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR45##

¹ H NMR (400 MHz, CDCl₃) δ2.85 (s, 12 H), 6.62 (d, 4 H), 7.26-7.56 (m, 9H), 7.76-7.88 (m, 3 H), 7.92 (d, 2 H); ESIMS, m/z for C₃₄ H₃₁ SN₅ M+H!⁺: 542.

EXAMPLE 63

2-trans-2-(2-benzthiazolyl)ethenylphenyl!-4-(4-N-dimethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole: ##STR46##

¹ H NMR (400 MHz, CDCl₃) δ2.80 (s, 3 H), 2.90 (s, 6 H), 6.53 (d, 2 H),6.64 (d, 4 H), 7.26-7.50 (m, 6 H), 7..54 (d, 2 H), 7.80 (d, 1 H), 7.85(d, 2 H), 7.93 (d, 1 H); ESIMS, m/z for C₃₃ H₂₉ SN₅ M+H!⁺ : 528.

EXAMPLE 64

2- trans-2-(2-cyano)ethenylphenyl!-4, 5-(4-N,N-dimethylaminophenyl)imidazole: ##STR47##

¹ H NMR (400 MHz, CDCl₃) δ2.95 (s, 12 H), 5.80 (d, 1 H), 6.65 (d, 4 H),7.40 (m, 7 H), 7.85 (br s, 2 H); ESIMS, m/z for C₂₈ H₂₇ N₅ M+H!⁺ : 434.

EXAMPLE 65

2- trans-2-(2-cyano)ethenylphenyl!-4-(4-N,N-dimethylaminophenyl)-5-4N-(2-methoxyethyl)amino)phenyl! imidazole: ##STR48##

¹ H NMR (400 MHz, CD₃ OD) δ2.92 (s, 6 H), 3.25 (m, 2 H), 3.34 (s, 3 H),3.54 (t, 2 H), 6.20 (d, 1 H), 6.60 (d, 2 H), 6.70 (d, 2 H), 7.26 (m, 4H), 7.50 (d, 1 H), 7.60 (d, 2 H), 7.96 (d, 2 H); ESIMS, m/z for C₂₉ H₂₉N₅ O M+H!⁺ : 464.

EXAMPLE 66

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N,N-diallylaminophenyl)5-(4-fluoro-phenyl)imidazole: ##STR49##

Compound 66 was prepared according the method C by using the properdione and aldehyde. Compound 66 has: ¹ H NMR (400 MHz, CDCl₃) δ3.76 (s,3 H), 3.91 (s, 4 H), 5.16 (m, 4 H), 5.83 (m, 2 H), 6.41 (d, 1 H), 6.63(d, 2 H), 6.96 (m, 2 H), 7.24 (d, 2 H), 7.57 (m, 5 H), 7.84 (d, 2 H);ESIMS, m/z for C₃₁ H₂₈ 0₂ N₃ F M+H!⁺ : 494.

EXAMPLE 67

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-methylaminophenyl)5-(4-pyrrolidinophenyl)imidazole: ##STR50##

Compound 67 was prepared according the method C by using the properdione and aldehyde. Compound 67 has: ¹ H NMR (400 MHz, CD₃ OD) δ1.96 (m,4 H), 2.74 (s, 3 H), 3.10 (s, 4 H), 3.78 (s, 3 H), 6.42-6.56 (m, 5 H),7.24 (dd, 4 H), 7.58 (d, 2 H), 7.64 (d, 1 H), 7.91 (d, 2 H); ESIMS, m/zfor C₃₀ H₃₀ O₂ N₄ M+H!⁺ : 479.

EXAMPLE 68

2-(trans-2-methoxycarbonyl-ethenylphenyl) -4-(4-N-methylaminophenyl)5-(4-piperidinophenyl) imidazole: ##STR51##

Compound 68 was prepared according the method C by using the properdione and aldehyde. Compound 68 has: ¹ H NMR (400 MHz, CD₃ OD) δ1.54 (m,2 H), 1.64 (m, 4 H), 2.74 (s, 3 H), 3.08 (s, 4 H), 3.78 (s, 3 H), 6.48(d, 1 H), 6.54 (d, 2 H), 6.85 (d, 2 H), 7.20 (d, 2 H), 7.31 (d, 2 H),7.58 td, 2 H), 7.63 (d, 1 H), 7,.91 (d, 2 H); ESIMS, m/z for C₃₁ H₃₂ O₂N₄ M+H!⁺ : 493.

EXAMPLE 69

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-4-N,N-di(2methoxyethyl)aminophenyl!-5-(4-N-methylaminophenyl) imidazole:##STR52##

¹ H NMR (400 MHz, CDCl₃) δ2.82 (s, 3 H), 3.30 (s, 6 H), 3.52 (m, 8 H),3.80 (s, 3 H), 6.42 (d, 1 H), 6.60 (m, 4 H), 7.30-7.60 (m, 6 H), 7.68(d, 1 H), 7.90 (br s, 2 H); ESIMS, m/z for C₃₂ H₃₆ O₄ N₄ M+H!⁺ : 541.

EXAMPLE 70

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-4-(1-imidazolyl)phenyl!-5(4-N-methylaminophenyl) imidazole: ##STR53##

¹ H NMR (400 MHz, CDCl₃) δ2.80 (s, 3 H), 3.72 (s, 3 H), 6.36 (d, 1 H),6.53 (d, 2 H), 7.06 (s, 1 H), 7.21 (d, 4 H), 7.48 (d, 2 H), 7.59 (d, 1H), 7.62 (d, 2 H), 7.74 (s, 1 H), 7.89 (d, 2 H); ESIMS, m/z for C₂₉ H₂₅O₂ N₅ M+H!⁺ : 476.

EXAMPLE 71

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4, 5-bis(4-N-morpholinophenyl) imidazole: ##STR54##

¹ H NMR (400 MHz, CDCl₃) δ3.10 (t, 8 H), 3.74 (s, 3 H), 3.79 (t, 8 H),6.36 (d, 1 H), 6.79 (d, 4 H), 7.36 (d, 4 H), 7.47 (d, 2 H), 7.59 (d, 1H), 7.86 (d, 2 H); ESIMS, m/z for C₃₃ H₃₄ O₄ N₄ M+H!⁺ : 551.

EXAMPLE 72

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-dimethylaminophenyl)-5-(4-N-morpholinophenyl)imidazole: ##STR55##

¹ H NMR (400 MHz, CDCl₃) δ2.90 (br s, 6 H), 3.10 (br s, 4 H), 3.76 (s, 3H), 3.82 (m, 4 H), 6.40 (d, 1 H), 6.65 (d, 2 H), 6.81 (d, 2 H),7.28-7.56 (m, 6 H), 7.63 (d, 1 H), 7.84 (d, 2 H); ESIMS, m/z for C₃₁ H₃₂O₃ N₄ M+H!⁺ : 506.

EXAMPLE 73

2-(trans-2-methoxycarbonyl-ethenylphenyl)-4-(4-N-methylaminophenyl)5-(4-N-morpholinophenyl)imidazole: ##STR56##

¹ H NMR (400 MHz, CDCl₃) δ2.80 (br s, 3 H), 3.10 (m, 4 H), 3.76 (s, 3H), 3.82 (t, 4 H), 6.37 (d, 1 H), 6.52 (d, 2 H), 6.80 (d, 2 H),7.28-7.56 (m, 6 H), 7.61 (d, 1 H), 7.83 (d, 2 H); ESIMS, m/z for C₃₀ H₃₀0₃ N₄ M+H!⁺ : 495.

EXAMPLE 74

2- 4-(3-methoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimnethylaminophenyl) imidazole: ##STR57##

¹ H NMR (400 MHz, CD₃ OD) δ2.90 (s, 12 H), 3.35 (s, 3 H), 4.10 (d, 2 H),6.35 (m, 1 H), 6.65 (d, 1 H), 6.70 (d, 4 H), 7.30 (d, 4 H), 7.50 (d, 2H), 7.90 (d, 2 H); ESIMS, m/z for C₂₉ H₃₂ ON₄ M+H!⁺ : 453.

EXAMPLE 75

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR58##

¹ H NMR (400 MHz, CD₃ OD) δ1.10 (t, 3 H), 2.90 (s, 12 H), 3.50 (q, 2 H),4.10 (br s, 2 H), 6.35 (m, 1 H), 6.65 (d, 1 H), 6.70 (d, 4 H), 7.30 (brs, 4 H), 7.50 (d, 2 H), 7.90 (br s, 2 H); ESIMS, m/z for C₃₀ H₃₄ ON₄M+H!⁺ : 467.

EXAMPLE 76

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-dimethylaminophenyl)-5-(4-N-methylaminophenyl)imnidazole: ##STR59##

¹ H NMR (400 MHz, CD₃ OD) δ1.36 (t, 3 H), 2.90 (s, 3 H), 3.08 (s, 6 H),3.70 (q, 2 H), 4.28 (d, 2 H), 6.45 (m, 1 H), 6.71 (d, 2 H), 6.76 (d, 1H), 6.85 (d, 2 H), 7.39 (d, 2 H), 7.47 (d, 2 H), 7.60 (d, 2 H), 8.02 (d,2 H); ESIMS, m/z for C₂₉ H₃₂ ON₄ M+H!⁺ : 453.

EXAMPLE 77

2- 4-(3-benzyloxy-trans-1-propen-1-yl)phenyl!-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR60##

¹ H NMR (400 MHz, CD₃ OD) δ2.90 (s, 12 H), 4.17 (d, 2 H), 4.54 (s, 2 H),6.38 (m, 1 H), 6.64 (d, 1 H), 6.69 (d, 4 H), 7.30 (m, 9 H), 7.46 (d, 2H), 7.86 (d, 2 H); ESIMS, m/z for C₃₅ H₃₆ ON₄ M+H!⁺ : 529.

EXAMPLE 78

2-4-(3-phenoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-dimethylaminophenyl)-5-(4-N-methylaminopheny)imidazole: ##STR61##

¹ H NMR (400 MHz, CD₃ OD) δ2.70 (s, 3 H), 2.90 (s, 6 H), 4.68 (d, 2 H),6.48 (m, 1 H), 6.57 (d, 1 H), 6.72 (m, 4 H), 6.88 (t, 1 H), 6.94 (d, 1H), 7.24 (m, 4 H), 7.32 (d, 2 H), 7.48 (d, 2 H), 7.88 (d, 2 H).

EXAMPLE 79

2-{4-3-(3,4-dimethoxy-phenoxy)-trans-1-propen-1-yl!phenyl}-4-(4-N-dimethylaminophenyl)-5-(4-N-methylaminopheny)imidazole: ##STR62##

¹ H NMR (400 MHz, CD₃ OD) δ2.90 (s, 12 H), 3.70 (s, 3 H), 3.78 (s, 3 H),5.10 (m, 2 H), 6.30 (m, 1 H), 6.44 (s, 1 H), 6.70 (m, 6 H), 7.30 (m, 7H), 7.80 (d, 2 H).

EXAMPLE 80

2- 4-(3-N,N-diethylamino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR63##

¹ H NMR (400 MHz, CD₃ OD) δ1.10 (m, 6 H), 2.90 (s, 12 H), 3.28 (m, 4 H),4.70 (d, 2 H), 6.34 (m, 1 H), 6.65 (d, 1 H), 6.67 (d, 4 H), 7.30 (d, 4H), 7.46 (d, 2 H), 7.86 (d, 2 H).

EXAMPLE 81

2- 4-(3-N-morpholino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR64##

¹ H NMR (400 MHz, CD₃ OD) δ2.49 (br s, 4 H), 2.89 (s, 12 H), 3.15 (d, 2H), 3.67 (dd, 4 H), 6.29 (m, 1 H), 6.58 (d, 1 H), 6.69 (d, 4 H), 7.29(d, 4 H), 7.44 (d, 2 H), 7.86 (d, 2 H); ESIMS, m/z for C₃₂ H₃₇ ONs M+H!⁺: 508.

EXAMPLE 82

2- 4-(3-N-piperidino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR65##

¹ H NMR (400 MHz, CD₃ OD) δ1.45 (br s, 2 H), 1.60 (m, 4 H), 2.47 (br s,4 H), 2.89 (s, 12 H), 3.13 (d, 2 H), 6.30 (m, 1 H), 6.55 (d, 1 H), 6.69(d, 4 H), 7.29 (d, 4 H), 7.43 (d, 2 H), 7.86 (d, 2 H); ESIMS, m/z forC₃₃ H₃₉ N₅ M+H!⁺ : 506.

EXAMPLE 83

2- 4-(3-N,N-dimethylamino-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR66##

¹ H NMR (400 MHz, CD₃ OD) δ2.28 (s, 6 H), 2.89 (s, 12 H), 3.13 (d, 2 H),6.28 (m, 1 H), 6.56 (d, 1 H), 6.67 (d, 4 H), 7.29 (d, 4 H), 7.43 (d, 2H), 7.86 (d, 2 H); ESIMS, m/z for C₃₀ H₃₅ N₅ M+H!⁺ : 466.

EXAMPLE 84

2-{4- 3-(2-methoxy-ethoxy)-trans-1-propen-1-yl!phenyl}-4, 5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR67##

¹ H NMR (400 MHz, CD₃ OD) δ2.90 (s, 12 H), 3.34 (s, 3 H), 3.55 (m, 2 H),3.62 (m, 2 H), 4.16 (d, 2 H), 6.36 (m, 1 H), 6.64 (d, 1 H), 6.70 (d, 4H), 7.30 (d, 4 H), 7.46 (d, 2 H), 7.87 (d, 2 H); ESIMS, m/z for C₃₁ H₃₆O₂ N₄ M+H!⁺ : 497.

EXAMPLE 85

2- 4-(3-butoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR68##

¹ H NMR (400 MHz, CD₃ OD) δ0.91 (t, 3 H), 1.39 (m, 2 H), 1.56 (m, 2 H),2.09 (s, 12 H), 3.47 (t, 2 H), 4.10 (d, 2 H), 6.34 (m,. 1 H), 6.61 (d, 2H), 6.69 (d, 4 H), 7.29 (d, 4 H), 7.44 (d, 2 H), 7.86 (d, 2 H); ESIMS,m/z for C₃₂ H₃₈ ON₄ M+H!⁺ : 495.

EXAMPLE 86

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-diethylaminophenyl) imidazole: ##STR69##

¹ H NMR (400 MHz, CD₃ OD) δ1.10 (t, 12 H), 1.20 (t, 3 H), 3.30 (br s, 8H), 3.55 (q, 2 H), 4.08 (d, 2 H), 6.34 (m, 1 H), 6.58 (m, 5 H), 7.20 (d,4 H), 7.40 (d, 2 H), 7.80(d, 2 H); ESIMS, m/z for C₃₄ H₄₂ ON₄ M+H!⁺ :523.

EXAMPLE 87

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-diethylaminophenyl)5-(4-N-methylaminophenyl)imidazole: ##STR70##

¹ H NMR (400 MHz, CD₃ OD) δ1.10 (t, 6 H), 1.19 (t, 3 H), 2.74 (s, 3 H),3.33 (q, 4 H), 3.52 (q, 2 H), 4.10 (d, 2 H), 6.34 (m, 1 H), 6.59 (m, 5H), 7.25 (m, 4 H), 7.44(d, 2 H), 7.85 (d, 2 H); ESIMS, m/z for C₃₁ H₃₆ON₄ M+H!⁺ : 481.1

EXAMPLE 88

2- 4-(3-methoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-pyrrolidinophenyl) imidazole: ##STR71##

¹ H NMR (400 MHz, CD₃ OD) δ1.97 (m, 8 H), 3.28 (m, 8 H), 3.36 (s, 3 H),4.12 (d, 2 H), 6.35 (m, 1 H), 6.50 (d, 4 H), 6.62 (d, 1 H), 7.27 (d, 4H), 7.46 (d, 2 H), 7.87 (d, 2 H); ESIMS, m/z for C₃₃ H₃₆ ON₄ M+H!⁺ :505.

EXAMPLE 89

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-pyrrolidinophenyl)imidazole: ##STR72##

¹ H NMR (400 MHz, CD₃ OD) δ1.19 (t, 3 H), 1.97 (m, 8 H), 3.28 (m, 8 H),3.53 (q, 2 H), 4.12 (d, 2 H), 6.35 (m, 1 H), 6.50 (d, 4 H), 6.62 (d, 1H), 7.27 (d, 4 H), 7.46 (d, 2 H), 7.87 (d, 2 H); ESIMS, m/z for C₃₄ H₃₈ON₄ M+H!⁺ : 519.

EXAMPLE 90

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-dimethylaminophenyl)-5-(4-pyrrolidinophenyl)imidazole: ##STR73##

¹ H NMR (400 MHz, CD₃ OD) δ1.17 (t, 3 H), 1.91 (m, 4 H), 2.85 (s, 6 H),3.16 (br s, 4 H), 3.50 (q, 2 H), 4.07 (d, 2 H), 6.30 (m, 1 H), 6.43 (d,2 H), 6.57 (d, 1 H), 6.63 (d, 2 H), 7.21 (d, 2 H), 7.27 (d, 2 H), 7.40(d, 2 H), 7.82 (d, 2 H); ESIMS, m/z for C₃₂ H₃₆ ON₄ M+H!⁺ : 493.

EXAMPLE 91

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5(4-pyrrolidinophenyl)imidazole: ##STR74##

¹ H NMR (400 MHz, CD₃ OD) δ1.17 (t, 3 H), 1.91 (m, 4 H), 2.85 (s, 3 H),3.16 (br s, 4 H), 3.50 (q, 2 H), 4.07 (d, 2 H), 6.30 (m, 1 H), 6.43 (d,2 H), 6.57 (d, 1 H), 6.63 (d, 2 H), 7.21 (d, 2 H), 7.27 (d, 2 H), 7.40(d, 2 H), 7.82 (d, 2 H); ESIMS, m/z for C₃₁ H₃₄ ON₄ M+H!⁺ : 479.

EXAMPLE 92

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N-morpholinophenyl) imidazole: ##STR75##

¹ H NMR (400 MHz, CD₃ OD) δ1.18 (t, 3 H), 3.10 (br s, 8 H), 3.56 (m, 2H), 3.78 (br s, 8 H), 4.14 (d, 2 H), 6.38 (m, 1 H), 6.88 (d, 4 H), 7.36(d, 4 H), 7.48 (d, 2 H), 7.88 (d, 2 H); ESIMS, m/z for C₃₄ H₃₈ O₃ N₄M+H!⁺ : 551.

EXAMPLE 93

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-dimethylaminophenyl)-5-(4-N-morpholinophenyl)imidazole: ##STR76##

¹ H NMR (400 MHz, CD₃ OD) δ1.18 (t, 3 H), 2.90 (br s, 6 H), 3.09 (m, 4H), 3.52 (q, 2 H), 3.76 (m, 4 H), 4.12 (d, 2 H), 6.34 (m, 1 H), 6.62 (d,1 H), 6.69 (d, 2 H), 6.86 (d, 2 H), 7.27 (d, 2 H), 7.34 (d, 2 H), 7.45(d, 2 H), 7.87 (d, 2 H); ESIMS, m/z for C₃₂ H₃₆ O₂ N₄ M+H!⁺ : 509.

EXAMPLE 94

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5(4-N-morpholinophenyl) imidazole: ##STR77##

¹ H NMR (400 MHz, CD₃ OD) δ1.19 (t, 3 H), 2.73 (s, 3 H), 3.08 (m, 4 H),3.52 (q, 2 H), 3.76 (m, 4 H), 4.10 (d, 2 H), 6.34 (m, 1 H), 6.55 (d, 2H), 6.61 (d, 1 H), 6.85 (d, 2 H), 7.20 (d, 2 H), 7.34 (d, 2 H), 7.45 (d,2 H), 7.86 (d, 2 H); ESIMS, m/z for C₃₁ H₃₄ O₂ N₄ M+H!⁺ : 495.

EXAMPLE 95

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-methylaminophenyl)-5-(4-N-isopropylaminophenyl)imidazole: ##STR78##

¹ H NMR (400 MHz, CD₃ OD) δ1.15 (s, 3 H), 1.16 (s, 3 H), 1.18 (t, 3 H),2.74 (s, 3 H), 3.53 (m, 3 H), 4.10 (d, 2 H), 6.33 (m, 1 H), 6.56 (m, 4H), 6.60 (d, 1 H), 7.23 (t, 4 H), 7.44 (d, 2 H), 7.85 (d, 2 H); ESIMS,m/z for C₃₀ H₃₄ ON₄ M+H!⁺ : 467.

EXAMPLE 96

2- 4-trans-(2-methanesulfonyl-ethenyl)-phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR79##

¹ H NMR (400 MHz, CD₃ OD) δ2.90 (s, 12 H), 3.04 (s, 3 H), 6.70 (d, 4 H),7.28 (d, 1 H), 7..32 (d, 4 H), 7.58 (d, 1 H), 7.68 (d, 2 H), 8.00 (d, 2H); ESIMS, m/z for C₂₈ H₃₀ O₂ N₄ S M+H!⁺ : 487.

EXAMPLE 97

2-(4-N-morpholinophenyl)-4,5-bis (4-N,N-dimnethylaminophenyl) imidazole:##STR80##

¹ H NMR (400 MHz, CD₃ OD) δ2.85 (br s, 12 H), 3.10 (t, 4 H), 3.74 (t, 4H), 6.64 (d, 4 H), 6.92 (d, 2 H), 7.26 (d, 4 H), 7.76 (d, 2 H); ESIMS,m/z for C₂₉ H₃₃ ON₅ M+H!⁺ : 468.

EXAMPLE 98

2- 4-(5-ethylcarboxyisoxazol-3-yl)-phenyl!-4,5-bis(4-N,N-dimethylamainophenyl) imidazole: ##STR81##

The aldehyde was prepared from terephthaldehyde momo (diethyl acetal)according to a similar literature preparation (Cf. Moriya, O. et al J.Chem. Soc. Perkin Trans 1, 1994, 413.).

Imidazole 98 was prepared according to method C-1. Compound 96 has: ¹ HNMR (400 MHz, CD₃ OD) δ1.20 (t, 3 H), 2.90 (br s, 12 H), 4.40 (q, 2 H),6.90 (br s, 4 H), 7.30 (br s, 2 H), 7.58 (s, 1 H), 7.90 (br s, 4 H),8.30 (br s, 2 H); ESIMS, m/z for C₃₁ H₃₁ O₃ N₅ M+H!⁺ : 522.

EXAMPLE 99

2-4-trans-(2-methoxycarbonyl-ethenyl)phenyl!-4-(p-tolyl)-5-(4-N,N-diethylaminomethylphenyl)imidazole: ##STR82##

¹ H NMR (400 MHz, CDCl₃) δ1.01 (t, 6 H), 2.30 (s, 3 H), 2.51 (q, 4 H),3.54 (s, 2 H), 3.76 (s, 3 H), 6.38 (d, 1 H), 7.04-7.54 (m, 10 H), 7.62(d, 1 H), 7.92 (d, 2 H); ESIMS, m/z for C₃₁ H₃₃ O₂ N₃ M+H!⁺ : 480.

EXAMPLE 100

2- 4-trans-(2-methoxycarbonyl-ethenyl)phenyl!-4,5-bis(4-N,N-diethylaminomethylphenyl) imidazole: ##STR83##

¹ H NMR (400 MHz, CDCl₃) δ1.01 (t, 12 H), 2.51 (q, 8 H), 3.54 (s, 4 H),3.76 (s, 3 H), 6.40 (d, 1 H), 7.20-7.54 (m, 10 H), 7.64 (d, 1 H), 7.92(d, 2 H); ESIMS, m/z for C₃₅ H₄₂ O₂ N₄ M+H!⁺ : 551.

EXAMPLE 101

2- 4-trans-(2-methoxycarbonyl)cyclopropan-1-yl!-4,5-bis(4-N,N-diethylaminomethylphenyl) imidazole: ##STR84##

¹ H NMR (400 MHz, CD₃ OD) δ1.38 (m, 1 H), 1.53 (m, 1 H), 1.92 (m, 1 H),2.48 (m, 1 H), 2.90 (s, 12 H), 3.68 (s, 3 H), 6.69 (d, 4 H), 7.17 (d, 2H), 7.28 (d, 4 H), 7.82 (d, 2 H); ESIMS, m/z for C₃₀ H₃₂ O₂ N₄ M+H!⁺ :481.

EXAMPLE 102

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-dimethoxyphenyl)imidazole: ##STR85##

¹ H NMR (400 MHz, CD₃ OD) δ1.18 (t, 3 H), 3.50 (q, 2 H), 3.72 (s, 6 H),4.08 (d, 2 H), 6.33 (m, 1 H), 6.58 (d, 1 H), 6.82 (d, 4 H), 7.32 (d, 4H), 7.42 (d, 2 H), 7.85 (d, 2 H); ESIMS, m/z for C₂₈ H₂₈ O₃ N₂ M+H!⁺ :441.

EXAMPLE 103

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis (4-diethoxyphenyl)imidazole: ##STR86##

¹ H NMR (400 MHz, CD₃ SOCD₃) δ1.18 (t, 3 H), 1.32 (t, 6 H), 3.52 (q, 2H), 3.96 (q, 4 H), 4.10 (d, 2 H), 6.33 (m, 1 H), 6.61 (d, 1 H), 6.81 (d,4 H), 7.31 (d, 4 H), 7.45 (d, 2 H), 7.86 (d, 2 H); ESIMS, m/z for C₃₀H₃₂ O₃ N₂ M+H!⁺ : 469.

EXAMPLE 104

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4diisopropyloxyphenyl) imidazole: ##STR87##

¹ H NMR (400 MHz, CD₃ OD) δ1.18 (t, 3 H), 1.25 (d, 12 H), 3.51 (q, 2 H),4.10 (d, 2 H), 4.53 (m, 2 H), 6.32 (m, 1 H), 6.60 (d, 1 H), 6.80 (d, 4H), 7.31 (d, 4 H), 7.43 (d, 2 H), 7.86 (d, 2 H); ESIMS, m/z for C₃₂ H₃₆O₃ N₂ M+H!⁺ : 497.

EXAMPLE 105

1-(3-imidazole-1-yl-propyl)-2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5bis (4-dimethoxyphenyl)imidazole: ##STR88##

¹ H NMR (400 MHz, CD₃ OD) δ1.20 (t, 3 H), 1.75 (m, 2 H), 3.55 (q, 2 H),3.68 (m, 5 H), 3.82 (s, 3 H), 3.88 (t, 2 H), 4.14 (d, 2 H), 6.41 (m, 1H), 6.70 (m, 5 H), 6.97 (d, 2 H), 7.21 (d, 2 H), 7.28 (d, 2 H), 7.30 (s,1 H), 7.50 (s, 4 H); ESIMS, m/z for C₃₄ H₃₆ O₃ N₄ M+H!⁺ : 549.

EXAMPLE 106

1-(3-imidazole-1-yl-propyl)-2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5bis (4-diethoxyphenyl)imidazole: ##STR89##

¹ H NMR (400 MHz, CD₃ OD) δ1.20 (t, 3 H), 1.29 (t, 3 H), 1.39 (t, 3 H),1.74 (m, 2 H), 3.55 (q, 2 H), 3.66 (t, 2 H), 3.86 (t, 2 H), 3.91 (q, 2H), 4.04 (q, 2 H), 4.14 (d, 2 H), 6.41 (m, 1 H), 6.67 (m, 5 H), 6.94 (d,2 H), 7.18 (d, 2 H), 7.27 (d, 2 H), 7.31 (s, 1 H), 7.50 (s, 4 H); ESIMS,m/z for C₃₆ H₄₀ O₃ N₄ M+H!⁺ : 577.

EXAMPLE 107

1-(3-imidazole-1-yl-propyl)-2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5bis (4-diisopropyloxyphenyl)imidazole: ##STR90##

¹ H NMR (400 MHz, CD₃ OD) δ1.20 (t, 3 H), 1.20 (d, 6 H), 1.30 (d, 6 H),1.74 (m, 2 H), 3.54 (q, 2 H), 3.65 (t, 2 H), 3.85 (t, 2 H), 4.14 (d, 2H), 4.47 (m, 1 H), 4.60 (m, 1 H), 6.40 (m, 1 H), 6.67 (m, 5 H), 6.93 (d,2 H), 7.17 (d, 2 H), 7.28 (d, 2 H), 7.34 (s, 1 H), 7.50 (s, 4 H); ESIMS,m/z for C₃₈ H₄₄ O₃ N₄ M+H!⁺ : 605.

Method C-2 ##STR91##

Imidazoles of this type were synthesized in the following way:

The appropriate substituted phenylglyoxal and aldehyde (equal molaramount to the phenylglyoxal)) were stirred in methanolic ammonia at roomtemperature (TLC mornitored). At completion, the reaction mixturediluted with ethyl acetate and washed with water (×2). The organic layerwas then washed with hydrochloric acid (2N) until no more desiredcompound in the organic layer. The aqueous layer was then neutralizedwith aqueous NaOH (2N), and extracted with CH₂ CL₂ (×2). The organiclayer was dried (Na₂ SO₄) and evaporated. Further chromatographicpurification then gave the desired compound. The following compoundswere synthesized in this way:

EXAMPLE 108

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-diethylphenyl)imidazole: ##STR92##

¹ H NMR (400 MHz, CD₃ OD) δ1.10 (t, 6 H), 1.17 (t, 3 H), 3.30 (q, 4 H),3.49 (q, 2 H), 4.08 (d, 2 H), 6.31 (m, 1 H), 6.58 (d, 1 H), 6.68 (d, 2H), 7.18 (s, 1 H), 7.42 (d, 2 H), 7.50 (d, 2 H), 7.82 (d, 2 H); ESIMS,m/z for C₂₄ H₂₉ ON₃ M+H!⁺ : 376.

EXAMPLE 109

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-methoxyphenyl)imidazole: ##STR93##

¹ H NMR (400 MHz, CD₃ OD) δ1.18 (t, 3 H), 3.51 (q, 2 H), 3.78 (s, 3 H),4.08 (d, 2 H), 6.32 (m, 1 H), 6.59 (d, 1 H), 6.90 (d, 2 H), 7.29 (s, 1H), 7.44 (d, 2 H), 7.62 (d, 2 H), 7.82 (d, 2 H); ESIMS, m/z for C₂₁ H₂₂O₂ N₂ M+H!⁺ : 335.

Method C-3

EXAMPLE 111

2- 4-trans-(2-N,N-dimnethylcarbonyl)-ethenyl!phenyl}-4,5-bis(4-N-dimethylaminophenyl) imidazole: ##STR94##

To a solution of compound 110 (100 mg, 0.22 mmol) in dichloromethane(5.0 mL) was added dimethylamine hydrochloride (54 mg, 0.66 mmol), EDCI(51 mg, 0.26 mmol), and DMAP (40 mg, 0.33 mmol). After stirringovernight at room temperature (23° C.), the solution was diluted withethyl acetate and washed with water. The organic layer was dried (Na₂SO₄), and evaporated. The residue was purified via preparative TLC togive the desired compound as a yellow solid. Compound 111 has ¹ H NMR(400 MHz, CD₃ OD) δ2.92 (s, 12 H), 3.03 (s, 3 H), 3.22 (s, 3 H), 6.72(d, 4 H), 7.16 (d, 1 H), 7.32 (d, 4 H), 7.55 (d, 1 H), 7.75 (d, 2 H),7.96 (d, 2 H); ESIMS, m/z for C₃₀ H₃₃ ON₅ M+H!⁺ : 480.

Method C-4

EXAMPLE 113

2- 4-(3-hydroxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR95##

DIBAL-H (1.0M in DCM, 1.76 ml, 1.76 mmol) was added dropwise to asolution of compound 112 DCM (207 mg, 0.44 mmol) at -78° C. After 1 h at78° C., aqueous sodium hydroxide (1.0M, 20 mL) was added and the mixturewas warmed to 23° C. Layers were separated and the aqueous layer wasextracted with DCM (×2). The combined organic layers were dried (Na₂SO₄) and evaporated. Purification on preparative TLC gave the desiredcompound 113 159 mg, as a yellow solid. Compound 113 has: ¹ H NMR (400MHz, CD₃ OD) δ2.90 (s, 12 H), 4.20 (d, 2 H), 6.38 (m, 1 H), 6.59 (d, 1H), 6.67 (d, 4 H), 7.28 (d, 4 H), 7.43 (d, 2 H), 7.85 (d, 2 H); ESIMS,m/z for C₂₈ H₃₀ ON₄ M+H!⁺ : 439.

Method C-5

EXAMPLE 114

1-methyl-2- 4-(3-hydroxy-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR96##

A suspention of compound 113 (11 mg, 0.026 mmol), methyliodide (31 mL,0.031 mmol), silver oxide (excess) in DMF was stirred at 23° C.overnight. The mixture was then diluted with DCM and washed with water.). The organic layer was dried (Na₂ SO₄) and evaporated. Purification onpreparative TLC gave the desired compound, 4.0 mg, as a yellow solid.Compound 114 has: ¹ H NMR (400 MHz, CD₃ OD) δ2.84 (s, 6 H), 2.96 (s, 6H), 3.45 (s, 3 H), 4.23 (d, 2 H), 6.45 (m, 1 H), 6.63 (d, 2 H), 6.66 (d,1 H), 6.80 (d, 2 H), 7.15 (d, 2 H), 7.27 (d, 2 H), 7.53 (d, 2 H), 7.63(d, 2 H); ESIMS, m/z for C₂₉ H₃₂ ON₄ M+H!⁺ : 453.

Method C-6

EXAMPLE 115

2- 4-(3-pivalate-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR97##

Compound 114 was prepared via acylation of allylic alcohol 113 A mixtureof pivaloyl chloride (0.1M) and triethylamine (0.15M) (0.55 mL) wasadded to a solution of allylic alcohol 113 (20 mg, 0.045 mmol) in DCM.at -20° C. The resulting mixture was stirred for 30 min, diluted withDCM, washed with water. The organic layer was dried (Na₂ SO₄) andevaporated. Purification on preparative TLC gave the desired compound115 5 mg, as a yellow solid. Compound 115 has: ¹ H NMR (400 MHz, CD₃ OD)δ1.10 (s, 9 H), 2.90 (s, 12 H), 4.70 (d, 2 H), 6.34 (m, 1 H), 6.65 (d, 1H), 6.67 (d, 4 H), 7.30 (d, 4 H), 7.48 (d, 2 H), 7.85 (d, 2 H); ESIMS,m/z for C₃₃ H₃₈ O₂ N₄ M+H!⁺ : 523.

Method C-7

EXAMPLE 116

2- 4- (3-methylcarbonyl-trans-1-propen-1-yl)phenyl!-4,5-bis(4-N,N-dimethylaminophenyl) imidazole: ##STR98##

Methylmagnesium bromide (1.0M, in dibutylether, 0.63 mL, 0.65 mmol) wasadded to solution of compound 112 in THF (5.0 mL) at -78 ° C. Afterstirring overnight under argon, during which time the mixture was warmedto 23° C., it was diluted with water and extracted with DCM. Thecombined organic layers were dried (Na₂ SO4) and evaporated.Purification on preparative TLC gave the desired compound as a yellowsolid. Compound 116 has: ¹ H NMR (400 MHz, CD₃ OD) δ2.36 (s, 3 H), 2.92(s, 12 H), 6.71 (d, 4 H), 6.80 (d, 1 H), 7.31 (d, 4 H), 7.64 (d, 1 H),7.70 (d, 2 H), 7.98 (d, 2 H); ESIMS, m/z for C₂₉ H₃₀ ON₄ M+H!⁺ : 451.

Method C-8

EXAMPLE 118

2- 4-(3-methylcarbonyl-trans-1-propen-1-yl)phenyl!-5-methoxybenzimidazole: ##STR99##

compound 118 was prepared according to a known procedure (Lee, M. et alMed. Chem.Res. 1993, 2, 79-86). Compound 118 has: ¹ H NMR (400 MHz, CD₃OD) δ1.20 (t, 3 H), 3.54 (q, 2 H), 3.81 (s, 3 H), 4.13 (d, 2 H), 6.41(m, 1 H), 6.66 (d, 1 H), 6.86 (m, 1 H), 7.04 (d, 1 H), 7.44 (d, 1 H),7.53 (d, 2 H), 7.96 (d, 2 H); ESIMS, m/z for Cl₉ H₂₀ O₂ N₂ M+H!⁺ : 309.

EXAMPLE 119

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4,5-bis-(4-N-isopropylaminophenyl)imidazole,

Compound 119 was prepared according to method C-1 by using theappropriate starting materials. ##STR100##

¹ H NMR (400 MHz, CD₃ OD) δ1.15 (d, 6 H), 1.16 (d, 6 H), 1.18 (t, 3 H),3.53 (m, 4 H), 4.10 (br s, 2 H), 6.33 (br s, 1 H), 6.56 (m, 5 H), 7.23(d, 4 H), 7.44 (d, 2 H), 7.85 (d, 2 H); ESIMS, m/z for C₃₂ H₃₈ ON₄ M+H!⁺: 495.

EXAMPLE 120

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-ethylaminophenyl)-5(4-N-isopropylaminophenyl) imidazole,

Compound 120 was prepared according to method C-1 by using theappropiate starting materials. ##STR101##

¹ H NMR (400 MHz, CD₃ OD) δ1.16 (m, 12 H), 3.07 (q, 2 H), 3.53 (m, 3 H),4.10 (d, 2 H), 6.33 (m, 1 H), 6.56 (m, 5 H), 7.23 (d, 4 H), 7.44 (d, 2H), 7.85 (d, 2 H); ESIMS, m/z for C₃₁ H₃₆ ON₄ M+H!⁺ : 481.

EXAMPLE 121

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-fluorophenyl)-5-(4-N-isopropylaminophenyl)imidazole,

Compound 121 was prepared according to method C-1 by using theappropriate starting materials. ##STR102##

¹ H NMR (400 MHz, CD₃ OD) δ1.16 (m, 9 H)), 3.52 (m, 3 H), 4.09 (d, 2 H),6.32 (m, 1 H), 6.56 (d, 2 H), 6.58 (d, 1 H), 6.98 (dd, 2 H), 7.14 (d, 2H), 7.45 (m, 4 H), 7.85 (d, 2 H); ESIMS, m/z for C₂₉ H₃₀ FON₃ M+H!⁺ :456.

EXAMPLE 122

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N,N-dipropylphenyl)imidazole,

Compound 122 was prepared according to method C-2 by using theappropriate starting materials. ##STR103##

¹ H NMR (400 MHz, CD₃ OD) δ0.91 (t, 6 H), 1.19 (t, 3 H), 1.58 (m, 4 H),3.26 (m, 4 H), 3.53 (m, 2 H), 4.11 (d, 2 H), 6.35 (m, 1 H), 6.63 (d, 1H), 6.66 (d, 1 H), 7.19 (s, 1 H), 7.48 (m, 4 H), 7.83 (d, 2 H); ESIMS,m/z for C₂₆ H₃₃ ON₃ M+H!⁺ : 404.

EXAMPLE 123

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-isopropylphenyl)imidazole,

Compound 123 was prepared according to method C-2 by using theappropriate starting materials. ##STR104##

¹ H NMR (400 MHz, CD₃ OD) δ1.16 (d, 6 H), 1.19 (t, 3 H), 3.53 (q, 2 H),3.60 (m, 1 H), 4.11 (d, 2 H), 6.35 (m, 1 H), 6.62 (d, 1 H), 6.64 (d, 2H), 7.19 (s, 1 H), 7.46 (m, 4 H), 7.83 (d, 2 H); ESIMS, m/z for C₂₃ H₂₇ON₃ M+H!⁺ : 362.

EXAMPLE 124

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4- (4-N-isobutylphenyl)imidazole,

Compound 124 was prepared according to method C-2 by using theappropriate starting materials. ##STR105##

¹ H NMR (400 MHz, CD₃ OD) δ0.94 (d, 6 H), 1.19 (t, 3 H), 1.87 (m, 1 H),2.90 (d, 2 H), 3.53 (q, 2 H), 4.12 (d, 2 H), 6.35 (m, 1 H), 6.62 (m, 3H), 7.18 (s, 1 H), 7.46 (m, 4 H), 7.83 (d, 2 H); ESIMS, m/z for C₂₄ H₂₉ON₃ M+H!⁺ : 376.

EXAMPLE 125

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-morpholinophenyl)imidazole,

Compound 125 was prepared according to method C-2 by using theappropriate starting materials. ##STR106##

¹ H NMR (400 MHz, CD₃ OD) δ1.19 (t, 3 H), 3.13 (t, 4 H), 3.53 (q, 2 H),3.80 (t, 4 H), 4.12 (d, 2 H), 6.35 (m, 1 H), 6.63 (d, 1 H), 6.97 (d, 2H), 7.29 (s, 1 H), 7.47 (d, 2 H), 7.61 (d, 2 H), 7.84 (d, 2 H); ESIMS,m/z for C₂₄ H₂₇ O₂ N₃ M+H!⁺ : 390.

EXAMPLE 126

2- 4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-4-N-(N'-ethyl)piperizanophenyl) imidazole,

Compound 126 was prepared according to method C-2 by using theappropriate starting material ##STR107##

¹ H NMR (400 MHz, CD₃ OD) δ1.16 (m, 6 H), 2.61 (q, 2 H), 2.78 (t, 4 H),3.26 (t, 4 H), 3.54 (q, 2 H), 4.12 (d, 2 H), 6.36 (m, 1 H), 6.64 (d, 1H), 7.00 (d, 2 H), 7.30 (s, 1 H), 7.48 (d, 2 H), 7.62 (d, 2 H), 7.84 (d,2 H); ESIMS, m/z for C₂₆ H₃₂ ON₄ M+H!⁺ : 417.

EXAMPLE 127

2-4-(3-ethoxy-trans-1-propen-1-yl)phenyl!-4-(4-N-morpholinophenyl)-5methyl-imidazole.

Compound 127 was prepared according to method C-1 by using theappropriate starting material ##STR108##

¹ H NMR (400 MHz, CD₃ OD) δ1.19 (t, 3 H), 2.34 (s, 3 H), 3.11 (t, 4 H),3.52 (q, 2 H), 3.79 (t, 4 H), 4.10 (d, 2 H), 6.34 (m, 1 H), 6.60 (d,IH), 6.98 (d, 2 H), 7.44 (m, 4 H), 7.80 (d, 2 H); ESIMS, m/z for C₂₅ H₂₉O₂ N₃ M+H!⁺ : 404.

The compounds described herein are capable of sensitizing multi-drugresistant tumor cells to antitumor chemotherapeutic agents, such asdoxorubicin and vinblastine. They also have the ability to potentiatethe sensitivity of tumor cells susceptible to these chemotherapeuticagents. This invention also relates to a method of sensitizingmultidrug-resistant tumor cells to antitumor chemotherapeutic agents. Italso relates to a method of increasing the sensitivity ofdrug-susceptible tumor cells to antitumor chemotherapeutic agents. Inaddition, this invention relates to a method of preventing the emergenceof MDR tumor cells during a course of treatment with antitumorchemotherapeutic agents. Finally, this invention relates to a method ofreducing the effective dosage of an antitumor chemotherapeutic agentduring a course of treatment. It has been found that compounds ofFormula 1 have the ability to increase the sensitivity of MDR mammaliancells in culture.

Cytotoxic drugs are commonly used as antitumor chemotherapeutic agents.These agents are also called antiproliferative agents. The desiredeffect of cytotoxic drugs is selective cell death with destruction ofthe malignant neoplastic cells and relative sparing of normal cells.

Cytotoxic drugs have also proved valuable in the treatment of otherneoplastic disorders including connective or autoimmune diseases,metabolic disorders, dermatological diseases, and DNA virus infections.

Proper use of cytotoxic drugs requires a thorough familiarity with thenatural history and pathophysiology of the disease before selecting thecytotoxic agent, determining a dose, and undertaling therapy. Eachpatient must be carefully evaluated, with attention directed towardfactors which may potentiate toxicity, such as overt or occultinfections, bleeding dyscrasias, poor nutritional status, and severemetabolic disturbances. In addition, the functional condition of certainmajor organs, such as liver, kidneys, and bone marrow, is extremelyimportant. Therefore, the selection of the appropriate cytotoxic agentand devising an effective therapeutic regimen is influenced by thepresentation of the patient.

Cytotoxic drugs as antitumor chemotherapeutic agents can be subdividedinto several broad categories, including, (1) alkylating agents, such asmechlorethamine, cyclophosphamide, melphalan, uracil mustard,chlorambucil, busulfan, carmustine, lomustine, semustine,streptozoticin, and decrabazine; (2) antimetabolites, such asmethotrexate, fluorouracil, fluorodeoxyuridine, cytarabine, azarabine,idoxuridine, mercaptopurine, azathioprine, thioguanine, and adeninearabinoside; (3) natural product derivatives, such as vinblastine,vincristine, dactinomycin, daunorubicin, doxorubicin, mithramycin,bleomycin, etoposide, teniposide, and mitomycin-C; and (4) miscellaneousagents, such as hydroxyurea, procarbezine, mititane, and cis-platinum.

Important antitumor chemotherapeutic agents (with the usual effectivedosage) to which clinical multidrug-resistance has been observed includevinblastine (0.1 mg per kilogram per week), vincristine (0.01 mg perkilogram per week), etoposide (35 to 50 mg per square meter per day),dactinomycin (0.15 mg per kilogram per day), doxorubicin (500 to 600 mgper square meter per week), daunorubicin (65 to 75 mg per square meterper week), and mithramycin (0.025 mg per kilogram per day). MDR has beenshown to occur in vitro as well as in the clinic.

Multidrug-resistant cell lines are easily obtainable for in vitrodetermination of drug sensitization by compounds of the presentinvention. In vitro potentiation of antineoplastic cytotoxicity by theimidazole derivatives of the present invention was measured in bothCEM/VLB1000 and SK/VLB1000 cell lines. The multidrug resistant celllines were obtained from Dr. Victor Ling, Ontario Cancer Institute,Toronto, Canada. The CEM/VLB 1000 cell line was maintained as asuspension in minimum essential medium supplemented with 10% fetalbovine serum in a humidied atmosphere of 95% air and 5% CO₂ while theSK/VLB 1000 cell line was maintained as adherent cells using theidentical medium conditions as the CEM cells. The CEM/VLB 1000 cellswere seeded at a density of 5×10⁴ cells/well in a 96 well microtiterplate while the SK/VLB 1000 cell line was seeded at a density of 2,500cells/well after trypsinization. Vinblastine (5 μg/mL, for the CEMcells) or Taxol (3 μg/mL, for the SK cells) and compound (0.01 to 50 μM)were added directly to the wells. After an incubation of 48 hours inpresence of drug, alamar blue (B. Page et al., Int. J. OncoL 3: 473-476,1993) was added (10 μL to the 200 μL cell suspension) for a period of 24hours after which the fluorescence (excitation=530 nM, emission=590 nM)was read for each well using a "CytoFluor" microtiter fluorometer platereader. This assay measures the effective concentration of compoundnecessary to enhance the cytotoxicity (EC₅₀) of vinblastine in the MDRcell line. The compounds of the present invention had EC₅₀ values in therange of 0.06 to 10 μM.

³ H-vinblastine accumulation was also measured in the CEM/VLB1000 cellline. Corning Easy-Wash 96 well plates were pretreated with PBS and 1%BSA for 60 minutes and then removed. CEM/VLB1000 cells were seeded at2×10⁵, 40 μL volume. Plates were incubated at 37° C. for 30-60 minutesprior to use. The reference reversing agent, verapamil, or the compoundof the present invention was added to the well followed by addition ofmedia containing ³ H-vinblastine (final concentration=275 nM). Plateswere allowed to incubate for 3 hours at 37° C. Cells were harvested ontopretreated Wallace filtermats A (pretreated with 0.1% polyethyleneimine)using a TomTek harvester-96. After filtering, the filtermats wereallowed to dry completely. Meltix B scintillant was then added to thefiltermats. The filters were then placed in a 90° C. oven forapproximately 3-5 minutes and then removed. Scintillant was allowed tosolidify on the filtermats. Filtermats were then placed in sample bagsand read on a Wallace BetaPlate scintillation counter. The effects ofcompounds of the present invention in the cytotoxicity potentiationassays and vinblastine (VLB) accumulation assay are given in the Tablebelow:

    ______________________________________                                                   Cytotocicity  .sup.3 H!VLB                                                    Potentiation (μM).sup.1                                                                 Accumulation (μM).sup.2                            Examples   CEM/VLB1000  CEMVLB1000                                            ______________________________________                                        56         0.55         `NT.sup.3                                             57         0.21         NT                                                    58         0.47         NT                                                    59         0.55         NT                                                    60         0.45         NT                                                    61         0.16         NT                                                    62         1.03         NT                                                    63         0.32         NT                                                    64         0.55         NT                                                    65         0.25         NT                                                    66         0.85         NT                                                    67         0.098        NT                                                    68         0.39         NT                                                    69         0.33         NT                                                    70         0.50         NT                                                    71         0.37         NT                                                    72         0.32         NT                                                    73         0.34         NT                                                    74         0.13         2.0                                                   75         0.098        1.2                                                   76         0.11         NT                                                    77         0.34         1.2                                                   78         0.45         NT                                                    79         1.21         NT                                                    80         0.88         NT                                                    81         0.32         NT                                                    82         0.96         NT                                                    83         1.30         NT                                                    84         0.09         NT                                                    85         0.11         NT                                                    86         0.26         NT                                                    87         0.06         NT                                                    88         0.26         NT                                                    89         0.24         NT                                                    90         0.12         NT                                                    91         0.11         NT                                                    92         0.22         NT                                                    93         0.15         NT                                                    94         0.25         NT                                                    95         0.05         NT                                                    96         0.73         NT                                                    97         0.19         NT                                                    98         0.60         NT                                                    99         0.29         NT                                                    100        3.4          NT                                                    101        0.2          NT                                                    102        0.35         NT                                                    103        0.24         NT                                                    104        0.25         NT                                                    105        0.65         NT                                                    106        0.38         NT                                                    107        0.49         NT                                                    108        0.30         NT                                                    109        1.85         NT                                                    111        0.62         1.7                                                   113        0.41         3.9                                                   114        0.63         NT                                                    115        0.48         NT                                                    116        0.23         NT                                                    118        1.00         NT                                                    119        .067         NT                                                    120        .053         NT                                                    121        .12          NT                                                    122        .28          NT                                                    123        .34          NT                                                    124        .25          NT                                                    125        .37          NT                                                    126        .71          NT                                                    127        .33          NT                                                    ______________________________________                                         .sup.1 Values presented are the midpoint (EC.sub.50 ) of the minimum and      maximum cytotoxicity induced by 3-5 μg/mL vinblastine and the specific     compound of the present invention.                                            .sup.2 Values presented are the midpoint (EC.sub.50 ) of the minimum and      maximum increase in accumulation of .sup.3 Hvinblastine caused by the         specfic compound of the present invention.                                    .sup.3 NT = Not tested.                                                  

The modulation of multidrug-resistance demonstrated by the imidazolederivatives described herein provides a method of treatment ofmultidrug-resistant tumors. The multidrug-resistance modulatoryproperties of the compounds described herein also provides a method forthe prevention of the emergence of multi-drug resistant tumors duringthe course of cancer treatment. These same compounds additionallyprovide a method for reducing the required dosage of an antitumorchemotherapeutic agent.

All of the methods of this invention involve (1) the administration of acompound of Formula 1 prior to, together with, or subsequent to theadministration of an antitumor chemotherapeutic agent; and (2) theadministration of a combination of a compound of Formula 1 and anantitumor chemotherapeutic agent.

Thus, the compounds of Formula 1 are useful in the treatment ofmultidrug-resistant tumor cells or tumor cells in general, eitherseparately or in combination with an antitumor chemotherapeutic agent.These compounds may be administered orally, topically or parenterally indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants, and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques.

The present invention also has the objective of providing suitabletopical, oral, and parenteral pharmaceutical formulations for use in thenovel methods of treatment of the present invention. The compounds ofthe present invention may be administered orally as tablets, aqueous oroily suspensions, lozenges, troches, powders, granules, emulsions,capsules, syrups or elixirs. The composition for oral use may containone or more agents selected from the group of sweetening agents,flavouring agents, colouring agents and preserving agents in order toproduce pharmaceutically elegant and palatable preparations. The tabletscontain the acting ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, (1) inertdiluents, such as calcium carbonate, lactose, calcium phosphate orsodium phosphate; (2) granulating and disintegrating agents, such ascorn starch or alginic acid; (3) binding agents, such as starch, gelatinor acacia; and (4) lubricating agents, such as magnesium stearate,stearic acid or talc. These tablets may be uncoated or coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. Coating may also beperformed using techniques described in the U.S. Pat. Nos. 4,256,108;4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may be in the form of hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin. They may alsobe in the form of soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, such as peanut oil, liquid paraffinor olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexpicients may be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2)dispersing or wetting agents which may be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethylenoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In adition, fatty acids suchas oleic acid find use in the preparation of injectables.

A compound of Formula 1 may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperature but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of Formula 1 are employed.

Dosage levels of the compounds of the present invention are of the orderof about 0.5 mg to about 100 mg per kilogram body weight, with apreferred dosage range between about 20 mg to about 50 mg per kilogrambody weight per day (from about 25 mg to about 5 gms per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage will vary depending uponthe host treated and the particular mode of administration. For example,a formulation intended for oral administration to humans may contain 5mg to 1 g of an active compound with an appropriate and convenientamount of carrier material which may vary from about 5 to about 95percent of the total composition. Dosage unit forms will generallycontain between from about 5 mg to about 500 mg of active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

In addition, some of the compounds of the instant invention may formsolvates with water or common organic solvents. Such solvates areencompassed within the scope of the invention.

What is claimed is:
 1. A compound of the formula 1 ##STR109## whereinthe substituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow:A. when R₁ is selected from the group consisting of:(i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-,and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof:(a) phenyl, trans -2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,or in which the said phenyl group is mono- or disubstituted with amember selected from the group consisting of hydroxy, halo, C₀₋₄ alkyland C₁₋₄ alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆alkyloxy, substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl,wherein the substituents are selected from the group consisting of C₁₋₆alkoxy, C₁₋₆ alkylthio, or (c) C₁₋₁₁ CO₂ R₅, C₁₋₁₁ CONHR₅, trans-CH═CHCO₂ R₅, or trans-CH═CHCONH₅ wherein R₅ is C₁₋₁₁ alkyl, or phenylC₁₋₁₁ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy;then R₂ and R₃ are eachindependently selected from the group consisting of mono-, di, andtri-substituted phenyl wherein the substituents are independentlyselected from: (i) substituted C₁₋₆ alkyl, (ii) substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii)substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino, (v) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, N--C₁₋₆alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N-(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino,wherein the substituents are selected from the groupconsisting of (a) hydroxy, C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, (b) C₃₋₆alkenyloxy, C₃₋₆ alkenylamino, or (c) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, N--C₁₋₆alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino,or R₂ and R₃ taken together forming an aryl group orsubstituted aryl wherein the substituents are defined as above in(i)-(v); and R₄ is selected from the group consisting of: (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; or (iii) substituted aryl C₀₋₁₁, alkylwherein the aryl group is selected from phenyl, imidazolyl, furyl,thienyl in which the substituents are selected from A. (a-c); orB. whenR₁ is selected from the group consisting of: Mono-,di-, andtri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from the groupconsisting of phenyl, thienyl, and the substituents are selected fromthe group consisting of: (a) trans-2-substituted benzimidazolylethenyl,trans-2-substituted benzoxazolylethenyl, trans-2-substitutedbenzthiazolylethenyl, in which the substituents are selected from thegroup consisting of hydrogen, hydroxy, halo, trihalomethyl, C₁₋₄ alkyland C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₃₋₆ alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄alkyloxy-C₁₋₄ alkylamino, substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy,substituted C₁₋₄ alkyloxycarbonyl, substituted C₁₋₄ alkylamino,di(substituted C₁₋₄ alkyl)amino, substituted C₃₋₆ alkenylamino,di(substituted C₃₋₆ alkenyl)amino, wherein the substituents are asdefined above, (b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2alkenylsulfonyl ethenyl, trans-2- substituted alkylsulfonylethenyl, trans-2- substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂ R₅, trans- CH═CHCO₂ R₅,C₁₋₆ CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino, morpholino, piperazino, N--C₁₋₆ alkenylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆ CONR₆ R₇, or trans- CH═CHCONR₆R₇, wherein R₆ and R₇ are independently selected from the groupconsisting of C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy, hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆alkyl, amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)aminoC₂₋₆ alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆alkyl, substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, whereinthe substituents are selected from the group consisting of pyrrolidino,piperidino, morpholino, piperazino, N--C₁₋₆ alkenylpiperazino, N--C₃₋₆alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, N--(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)carbonyl C₂₋₆ alkenyl, in which R₇ is defined as above 2(d)!, (f)HO--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇ --O--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆ R₇ N--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH--C(O)--O--C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆ R₇ N--C(O)--O--C₁₋₆ alkyl-C₂₋₆alkenyl, R₇ O--C(O)--OC₁₋₆ alkyl-C₂₋₆ alkenyl, R₇ --C(O)--O--C₁₋₆alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined as above 2(d)!, (g) R₇--O--CO₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇ NH-- C₀₋₃ alkyl- C₃₋₆cycloalkan-1-yl, R₆ R₇ N-- C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl, R₇NH--C(O)--O-- C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆ R₇ N--C(O)--O-- C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇ O--C(O)--O-- C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl,R₇ --C(O)--O-- C₀₋₃ alkyl- C₃₋₆ cycloalkan-1-yl, R₇ O--C(O)--C₀₋₃alkyl--C₃₋₆ cycloalkan-1-yl, wherein R₇ and is defined as above2(d)!;then R₂ and R₃ are each independently selected from the groupconsisting of (1) hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₁₋₆ alkenyl, substituted C₀₋₆ alkenyl, C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy,C₁₋₆ alkylamino, substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino,substituted C₃₋₆ alkenylamino, (2) mono-, di-, and tri-substitutedphenyl wherein the substituents are independently selected from:(i)halo, trifluoromethyl, substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy,(iii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino,di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substitutedC₃₋₆ alkenyl)amino,or (iv) pyrrolidino, piperidino, morpholino,imidazolyl, substituted imidazolyl, piperazino, N--C₁₋₆alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino,wherein the substituents are selected from the groupconsisting of (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, N--C₁₋₆alkenylpiperazino, N--C₃₋₆ alkenylpiperazino, N--(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, N--(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, N--(C1-6alkylamino C₁₋₆ alkyl)piperazino, N--(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino;with the proviso that at least one of R₂ and R₃ groupbe selected from B (2)! and the phenyl and the substituents be selectedfrom (ii)-(v) above; or R₂ and R₃ taken together forming an aryl groupsuch as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of hydrogen, hydroxy,C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alklylamino, phenyl-C₁₋₆ alkylamino,C₁₋₆ alkoxycarbonyl and the substituents are selected from (ii)-(iv); or(c) aryl C₀₋₁₁ alkyl wherein the aryl group is selected from phenyl,imidazolyl, furyl, thienyl.or its pharmaceutically acceptable salts. 2.A compound according to claim 1 having the following formula: ##STR110##or its pharmaceutically acceptable salts.
 3. A compound according toclaim 1 having the following formula: ##STR111## or its pharmaceuticallyacceptable salts.
 4. A compound according to claim 1 having thefollowing formula: ##STR112## or its pharmaceutically acceptable salts.5. A compound according to claim 1 having the following formula:##STR113## or its pharmaceutically acceptable salts.
 6. A compoundaccording to claim 1 having the following formula: ##STR114## or itspharmaceutically acceptable salts.
 7. A compound according to claim 1having the following formula: ##STR115## or its pharmaceuticallyacceptable salts.
 8. A compound according to claim 1 having thefollowing formula: ##STR116## or its pharmaceutically acceptable salts.9. A compound according to claim 1 having the following formula:##STR117## or its pharmaceutically acceptable salts.
 10. A compoundaccording to claim 1 having the following formula: ##STR118## or itspharmaceutically acceptable salts.
 11. A compound according to claim 1having the following formula: ##STR119## or its pharmaceuticallyacceptable salts.
 12. A compound according to claim 1 having thefollowing formula: ##STR120## or its pharmaceutically acceptable salts.13. A compound according to claim 1 having the following formula:##STR121## or its pharmaceutically acceptable salts.
 14. A compoundaccording to claim 1 having the following formula: ##STR122## or itspharmaceutically acceptable salts.
 15. A compound according to claim 1having the following formula: ##STR123## or its pharmaceuticallyacceptable salts.
 16. A compound according to claim 1 having thefollowing formula: ##STR124## or its pharmaceutically acceptable salts.17. A compound according to claim 1 having the following formula:##STR125## or its pharmaceutically acceptable salts.
 18. A compoundaccording to claim 1 having the following formula: ##STR126## or itspharmaceutically acceptable salts.
 19. A compound according to claim 1having the following formula: ##STR127## or its pharmaceuticallyacceptable salts.
 20. A compound according to claim 1 having thefollowing formula: ##STR128## or its pharmaceutically acceptable salts.21. A compound according to claim 1 having the following formula:##STR129## or its pharmaceutically acceptable salts.
 22. A compoundaccording to claim 1 having the following formula: ##STR130## or itspharmaceutically acceptable salts.
 23. A compound according to claim 1having the following formula: ##STR131## or its pharmaceuticallyacceptable salts.
 24. A compound according to claim 1 having thefollowing formula: ##STR132## or its pharmaceutically acceptable salts.25. A compound according to claim 1 having the following formula:##STR133## or its pharmaceutically acceptable salts.
 26. A compoundaccording to claim 1 having the following formula: ##STR134## or itspharmaceutically acceptable salts.
 27. A compound according to claim 1having the following formula: ##STR135## or its pharmaceuticallyacceptable salts.
 28. A compound according to claim 1 having thefollowing formula: ##STR136## or its pharmaceutically acceptable salts.29. A compound according to claim 1 having the following formula:##STR137## or its pharmaceutically acceptable salts.
 30. A compoundaccording to claim 1 having the following formula: ##STR138## or itspharmaceutically acceptable salts.
 31. A compound according to claim 1having the following formula: ##STR139## or its pharmaceuticallyacceptable salts.
 32. A compound according to claim 1 having thefollowing formula: ##STR140## or its pharmaceutically acceptable salts.33. A compound according to claim 1 having the following formula:##STR141## or its pharmaceutically acceptable salts.
 34. A compoundaccording to claim 1 having the following formula: ##STR142## or itspharmaceutically acceptable salts.
 35. A compound according to claim 1having the following formula: ##STR143## or its pharmaceuticallyacceptable salts.
 36. A compound according to claim 1 having thefollowing formula: ##STR144## or its pharmaceutically acceptable salts.37. A compound according to claim 1 having the following formula:##STR145## or its pharmaceutically acceptable salts.
 38. A compoundaccording to claim 1 having the following formula: ##STR146## or itspharmaceutically acceptable salts.
 39. A compound according to claim 1having the following formula: ##STR147## or its pharmaceuticallyacceptable salts.
 40. A compound according to claim 1 having thefollowing formula: ##STR148## or its pharmaceutically acceptable salts.41. A compound according to claim 1 having the following formula:##STR149## or its pharmaceutically acceptable salts.
 42. A compoundaccording to claim 1 having the following formula: ##STR150## or itspharmaceutically acceptable salts.
 43. A compound according to claim 1having the following formula: ##STR151## or its pharmaceuticallyacceptable salts.
 44. A compound according to claim 1 having thefollowing formula: ##STR152## or its pharmaceutically acceptable salts.45. A compound according to claim 1 having the following formula:##STR153## or its pharmaceutically acceptable salts.
 46. A compoundaccording to claim 1 having the following formula: ##STR154## or itspharmaceutically acceptable salts.
 47. A compound according to claim 1having the following formula: ##STR155## or its pharmaceuticallyacceptable salts.
 48. A compound according to claim 1 having thefollowing formula: ##STR156## or its pharmaceutically acceptable salts.49. A compound according to claim 1 having the following formula:##STR157## or its pharmaceutically acceptable salts.
 50. A compoundaccording to claim 1 having the following formula: ##STR158## or itspharmaceutically acceptable salts.
 51. A compound according to claim 1having the following formula: ##STR159## or its pharmaceuticallyacceptable salts.
 52. A compound according to claim 1 having thefollowing formula: ##STR160## or its pharmaceutically acceptable salts.53. A compound according to claim 1 having the following formula:##STR161## or its pharmaceutically acceptable salts.
 54. A compoundaccording to claim 1 having the following formula: ##STR162## or itspharmaceutically acceptable salts.
 55. A compound according to claim 1having the following formula: ##STR163## or its pharmaceuticallyacceptable salts.
 56. A compound according to claim 1 having thefollowing formula: ##STR164## or its pharmaceutically acceptable salts.57. A compound according to claim I having the following formula:##STR165## or its pharmaceutically acceptable salts.
 58. A compoundaccording to claim 1 having the following formula: ##STR166## or itspharmaceutically acceptable salts.
 59. A compound according to claim 1having the following formula: ##STR167## or its pharmaceuticallyacceptable salts.
 60. A compound according to claim 1 having thefollowing formula: ##STR168## or its pharmaceutically acceptable salts.61. A compound according to claim 1 having the following formula:##STR169## or its pharmaceutically acceptable salts.
 62. A compoundaccording to claim 1 having the following formula: ##STR170## or itspharmaceutically acceptable salts.
 63. A compound according to claim 1having the following formula: ##STR171## or its pharmaceuticallyacceptable salts.
 64. A compound according to claim 1 having thefollowing formula: ##STR172## or its pharmaceutically acceptable salts.65. A compound according to claim 1 having the following formula:##STR173## or its pharmaceutically acceptable salts.
 66. A compoundaccording to claim 1 having the following formula: ##STR174## or itspharmaceutically acceptable salts.
 67. A compound according to claim 1having the following formula: ##STR175## or its pharmaceuticallyacceptable salts.
 68. A compound according to claim 1 having thefollowing formula: ##STR176## or its pharmaceutically acceptable salts.69. A compound according to claim 1 having the following formula:##STR177## or its pharmaceutically acceptable salts.
 70. A method oftreatment for increasing the sensitivity of tumor cells to anti-cancerchemotherapeutic agents, said tumor cells being susceptible toanticancer chemotherapeutic agents, and said tumor cells having becomeresistant to chemotherapy comprising administration to a mammalianspecies in need of such treatment a therapeutically effective amount ofa compound of claim 1 and a pharmaceutically acceptable carrier.
 71. Amethod of treatment of tumor cells, said tumor cells being susceptibleto anti-cancer chemotherapeutic agents, and said tumor cells havingbecome resistant to chemotherapy comprising: administration to amammalian species in need of such treatment, of a therapeuticallyeffective amount of said anti-cancer chemotherapeutic agent, and aneffective amount of a compound of claim
 1. 72. A method of treatment oftumor cells, comprising: administration to a mammalian species in needof such treatment a therapeutically effective amount of an anti-cancerchemotherapeutic agent selected from the group consisting of taxol,vinblastine, vincristine, daunorubicin, and doxorubicin and an effectiveamount of a compound according to claim
 62. 73. A pharmaceuticalcomposition for increasing the sensitivity of tumor cells to anti-cancerchemotherapeutic agents, said tumors cells having become resistant tochemotherapy comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 74. Apharmaceutical composition for increasing the sensitivity of tumor cellsto anti-cancer chemotherapeutic agents, said tumors cells having becomeresistant to chemotherapy comprising: a therapeutically effective amountof an anti-cancer chemotherapeutic agent selected from the groupconsisting of taxol, vinblastine, vincristine, daunorubicin, anddoxorubicin, an effective amount of a compound of claim 1, and apharmaceutically acceptable carrier.